Thiol compounds, their production and use

ABSTRACT

The present invention provides a compound represented by Formula:  
                 
 
     wherein ring A and ring B may be same or different and each is an optionally substituted homocyclic or heterocyclic ring and the like, each R 1  may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR 2 , etc., X 1  is a bond, an optionally substituted divalent C 1-3  aliphatic hydrocarbon group or —NR 3 —, etc, X 2  is a bond, an optionally substituted divalent C 1-3  aliphatic hydrocarbon group, —NR 4 —, —O— or —S(O) p — (wherein p is 0, 1 or 2), each Y may be same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR 5 , an oxo group, a thioxo group, an optionally substituted imino group, a nitro group, a cyano group, etc., each m may be same or different and is 0 or 1, n is an integer of 1 to 3, q 1  is an integer of 1 to 2n+4, q 2  is an integer of 0 to 2n+3, and the sum of q 1  and q 2  is 2n+4 or a salt thereof.

TECHNICAL FIELD

[0001] The present invention relates to a novel thiol derivative whichhas an excellent matrix metalloprotease inhibiting activity, and isuseful as a therapeutic agent or a prophylactic agent againstosteoarthritis and rheumatoid arthritis, and also as an agent forinhibiting the metastasis, the infiltration and the proliferation ofvarious cancers.

BACKGROUND ART

[0002] A matrix metalloprotease (MMP) is an endopeptidase playing aphysiologically important role in tissue reconstruction, and itsprotease activity is under strict control. However, such control isdisturbed in pathological conditions to induce an excessive degradationof the extracellular matrix, thus being involved pathogenically inarticular diseases such as osteoarthritis and rheumatoid arthritis, bonediseases such as osteoporosis, periodontosis, tumor infiltration ormetastasis, corneal ulceration and the like.

[0003] At least 15 types of MMPs are now known, and are classified basedon their primary structure and substrate specificity into 5 groupsconsisting of the collagenase group (MMP-1, 8, 13), the gelatinase group(MMP-2, 9), the stromelysin group (MMP-3, 10), the membrane-type MMPgroup (MT1, 2, 3, 4-MMP) and the miscellaneous group (MMP-7, 11, 12,18). Among these groups, MMP-13 in the collagenase group is reported tobe expressed exclusively in cartilage and bone tissues and produced at ahigher level in articular diseases.

[0004] In addition, MMP-13 is assumed to be deeply involved in bone orarticular diseases due to its higher collagen degrading activity whencompared with other collagenases.

[0005] A large number of MMP inhibitors have been reported (CurrentPharmaceutical Design, 2, 624-661 (1996), Expert Opinion on TherapeuticPatents, 6, 1305-1315 (1996), and a large number of thiol derivativeswere also reported recently (WO97-3783, WO97-38007, WO97-48685,EP818443, WO98-3164, WO98-3166, WO98-6696, WO98-8814, WO98-12211,WO98-23588, Bioorganic & Medicinal Chemistry Letters, 8, 1157-1162(1998), Bioorganic &Medicinal Chemistry Letters, 8, 1163-1168 (1998)).

[0006] Those also reported in a large number are the compoundsexhibiting inhibitory effects on MMP-13, which are classified broadlyinto hydroxamic acid derivatives (British Journal of Pharmacology, 121,540-546 (1997), WO97-31892, WO98-15525, WO98-16506, WO98-16520),carboxylic acid derivatives (Journal of Clinical Investigation, 99,1534-1545 (1997)-, WO98-6711, WO98-9934, WO98-17643) and thiolderivatives (WO98-3164, WO98-3166).

[0007] A novel compound which is more satisfactory when compared withconventional MMP inhibitors in terms of efficacy, duration and safety isdesired.

DISCLOSURE OF INVENTION

[0008] In the course of research under the circumstances describedabove, we finally discovered that, due to the chemical structurecharacterized substantially by the substitution of the nitrogen atom ona ring represented by Formula:

[0009] wherein each Y may be same or different and is a hydrogen atom,an optionally substituted hydrocarbon group, a halogen atom, a carboxylgroup, an acyl group, an optionally substituted hydroxy group, anoptionally substituted amino group, SR⁵ (wherein R⁵ is a hydrogen atom,an optionally substituted hydrocarbon group, an acyl group or anoptionally substituted heterocyclic group), an oxo group, a thioxogroup, an optionally substituted imino group, a nitro group or a cyanogroup, n is an integer of 1 to 3 and q₂ is an integer of 0 to 2n+3 witha group represented by Formula:

[0010] wherein ring A and ring B may be same or different and each is anoptionally substituted homocyclic or heterocyclic ring, wherein thesubstituents on ring A (or ring B) are bound to the position capable ofbeing substituted on ring B (or ring A) and taken together with ring A,ring B and X² to form a condensed ring, X¹ is a bond, an optionallysubstituted divalent C₁₃ aliphatic hydrocarbon group or —NR³— (whereinR³ is a hydrogen atom, an optionally substituted hydrocarbon group or anacyl group), X² is a bond, an optionally substituted divalent C₁₋₃aliphatic hydrocarbon group, —NR⁴— (wherein R⁴ is a hydrogen atom, anoptionally substituted hydrocarbon group or an acyl group), —O— or—S(O)_(p)— (wherein p is 0, 1 or 2);

[0011] and also by the substitution on the carbon atom capable of beingsubstituted on a ring represented by Formula:

[0012] wherein each symbol has a meaning described above with a grouprepresented by Formula:

[0013] wherein each R¹ may be same or different and is a hydrogen atom,an optionally substituted hydrocarbon group, an acyl group, anoptionally substituted heterocyclic group or SR² (wherein R² is ahydrogen atom, an optionally substituted hydrocarbon group, an acylgroup or an optionally substituted heterocyclic group), each m may besame or different and is 0 or 1, q₁ is an integer of 1 to 2n+4, acompound represented by Formula:

[0014] wherein ring A and ring B may be same or different and each is anoptionally substituted homocyclic or heterocyclic ring, wherein thesubstituents on ring A (or ring B) is bound to the position capable ofbeing substituted on ring B (or ring A) and taken together

[0015] with ring A, ring B and X² to form a condensed ring, each R¹ maybe same or different and is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group, an optionally substituted heterocyclicgroup or SR² (wherein R² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group), X¹ is a bond, an optionally substituted divalentC₁₋₃ aliphatic hydrocarbon group or —NR³— (whereinft R³ is a hydrogenatom, an optionally substituted hydrocarbon group or an acyl group), X²is a bond, an optionally substituted divalent C₁₋₃ aliphatic hydrocarbongroup, —NR⁴— (wherein R⁴ is a hydrogen atom, an optionally substitutedhydrocarbon group or an acyl group), —O— or —S(O)_(p)— (wherein p is 0,1 or 2), each Y may be same or different and is a hydrogen atom, anoptionally substituted hydrocarbon group, a halogen atom, a carboxylgroup, an acyl group, an optionally substituted hydroxy group, anoptionally substituted amino group, SR⁵ (wherein R⁵ is a hydrogen atom,an optionally substituted hydrocarbon group, an acyl group or anoptionally substituted heterocyclic group), an oxo group, a thioxogroup, an optionally substituted imino group, a nitro group or a cyanogroup, each m may be same or different and is 0 or 1, n is an integer of1 to 3, q₁ is an integer of 1 to 2n+4, q₂ is an integer of 0 to 2n+3,and the sum of q, and q₂ is 2n+4 or a salt thereof unexpectedly exhibitsan excellent MMP inhibiting effect (especially an MMP13 inhibitingeffect) resulting from its specific chemical structure in combinationwith excellent duration and safety, and such pharmacological effect isuseful in a prophylactic and therapeutic agent against osteoarthritis,rheumatoid arthritis, osteoporosis, cancer, periodontosis or cornealulcer, whereby establishing the invention.

[0016] Thus, the present invention is:

[0017] (1) a compound represented by Formula (I) shown above or a saltthereof (provided that when ring B is a nitrogen-containing heterocyclicring then X² binds to a position capable of being substituted except fora nitrogen atom on ring B);

[0018] (2) a compound of the above (1) wherein each of ring A and ring Bis an optionally substituted benzene ring;

[0019] (3) a compound of the above (1) wherein each R¹ may be same ordifferent and is a hydrogen atom, an optionally substituted lower alkylgroup, —(C═O)—R⁶ (wherein R⁶ is a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted amino group oran optionally substituted hydroxy group) or SR² (wherein R² has ameaning defined in claim 1);

[0020] (4) a compound of the above (1) wherein each R¹ may be same ordifferent and is represented by Formula:

[0021] wherein each symbol has a meaning defined in the above (1), or byformula:

[0022] wherein each symbol has a meaning defined in the above (1);

[0023] (5) a compound of the above (1) wherein X¹ is an optionallysubstituted methylene group;

[0024] (6) a compound of the above (1) wherein X² is —O—;

[0025] (7) a compound of the above (1) wherein the group represented byFormula:

[0026] in Formula I is a group represented by Formula:

[0027] wherein each of R⁷ to R¹¹ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹² (wherein R¹² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group) and each of the other symbols has a meaning definedin the above (1);

[0028] (8) a compound of the above (1) wherein the group represented byFormula:

[0029] in Formula I is a group represented by Formula:

[0030] wherein each of R¹³ to R²⁵ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹² (wherein R¹² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group) and each of the other symbols has a meaning definedin the above (1);

[0031] (9) a compound of the above (1) wherein m is 0;

[0032] (10) a compound of the above (1) which is represented by Formula:

[0033] wherein each symbol has a meaning defined in the above (1);

[0034] (11) a method for producing a compound represented by Formula:

[0035] wherein each symbol has a meaning defined in the above (1) or asalt thereof, comprising reacting a compound represented by Formula:

[0036] wherein L is a leaving group and each of the other symbols has ameaning defined in the above (1) or a salt thereof with a compoundrepresented by Formula:

R¹SH

[0037] wherein R¹ has a meaning defined in the above (1) or a saltthereof;

[0038] (12) a method for producing a compound represented by Formula:

[0039] wherein each symbol has a meaning defined in the above (1) or asalt thereof, comprising reacting a compound represented by Formula:

[0040] wherein each symbol has a meaning defined in the above (1) or asalt thereof, or a compound represented by Formula:

[0041] wherein each symbol has a meaning defined in the above (1) or asalt thereof, with a compound represented by Formula:

R¹SH

[0042] wherein R¹ has a meaning defined in the above (1) or a saltthereof;

[0043] (13) a pharmaceutical composition comprising a compoundrepresented by Formula (I) or a salt thereof;

[0044] (14) a matrix metalloprotease inhibitor comprising a compound ofthe above (13) or a salt thereof; and,

[0045] (15) a prophylactic and therapeutic agent against osteoarthritis,rheumatoid arthritis, osteoporosis, cancer, periodontosis or cornealulcer comprising a compound of the above (13) or a salt thereof.

[0046] When Compound (I) or a salt thereof contains an asymmetric carbonin its structure, its optically active forms and racemates are alsoencompassed in the invention, and Compound (I) or a salt thereof may bea hydrate or an anhydride.

[0047] The present invention is further detailed below.

[0048] Ring A and Ring B

[0049] Ring A and ring B may be same or different, and each is ahomocyclic or heterocyclic ring having a same or different substituent.Furthermore, the substituents on ring A (or ring B) may be bound to theposition capable of being substituted on ring B (or ring A) and takentogether with ring A, ring B and X² to form a condensed ring.

[0050] A “homocyclic or heterocyclic ring” includes, for example, (i) anaromatic heterocyclic ring or a non-aromatic heterocyclic ringcontaining, in addition to carbon atoms, 1 or 2 kinds of heteroatomsselected from nitrogen, sulfur and oxygen atoms, preferably the numberof heteroatoms is 1 to 3 and (ii) a cyclic hydrocarbon consisting ofcarbon atoms (homocyclic ring).

[0051] An “aromatic heterocyclic ring” may for example be a 5- or6-membered aromatic heterocylic ring containing, in addition to carbonatoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfuratoms (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole,oxazole, isoxazole, etc.).

[0052] A preferred aromatic heterocyclic ring may for example bepyridine, pyrazine and thiophene rings as well as pyrrole and thiazolerings, etc.

[0053] Those preferred especially are (i) a nitrogen-containingheterocyclic ring containing, in addition to carbon atoms, 1 to 2nitrogen atoms (for example, pyridine and pyrazine rings), or (ii) a5-membered aromatic heterocyclic ring containing, in addition to carbonatoms, 1 sulfur atom (for example, thiophene ring).

[0054] A “non-aromatic heterocyclic ring” described above includes a 5-to 9-membered non-aromatic heterocylic ring, preferably a 5- to6-membered non-aromatic heterocylic ring, containing, in addition tocarbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen andsulfur atoms.

[0055] Those “non-aromatic heterocyclic ring” may typically betetrahydropyridine, dihydropyridine, tetrahydropyrazine,tetrahydropyrimidine, tetrahydropyridazine, dihydropyrane,dihydropyrrole, dihydroimidazole, dihydropyrazol, dihydrothiophene,dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole,dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine,hexahydropyridazine, tetrahydropyrane, morpholine, pyrrolidine,imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran,tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole,tetrahydroisoxazole rings, etc.

[0056] A “cyclic hydrocarbon (homocyclic ring)” described above includesa 3- to 10-membered (preferably 5- to 9-membered) cyclic hydrocarbon,more preferably 5- to 6-membered cyclic hydrocarbon. Those which may beexemplified are benzene, a C₃₋₁₀ cycloalkene (for example, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), a C₃₋₁₀cycloalkane (for example cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, etc.), etc. A cycloalkene is preferably aC₅₋₆ cycloalkene (for example, cyclopentene, cyclohexene, etc.), while acycloalkane is preferably a C₅₋₆ cycloalkane (for example, cyclohexane,cyclopentane, etc.), etc. Each of ring A and ring B is preferably a6-membered homocyclic ring such as benzene and cyclohexene-rings, etc.,particularly a benzene ring.

[0057] A substituent which may be possessed by a “homocyclic orheterocyclic ring” represented by ring A and ring B may for example be:

[0058] (i) a halogen atom (for example, fluorine, chlorine, bromine,iodine atoms, etc.);

[0059] (ii) an optionally substituted alkyl group;

[0060] (iii) an optionally halogenated alkoxy group (for example, a C₁₋₆alkoxy group which is substituted optionally with a halogen atom such asfluorine and chlorine atoms, such as methoxy, difluoromethoxy,trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,perfluorobutoxy, pentyloxy, hexyloxy groups);

[0061] (iv) an optionally halogenated alkylthio group (for example, aC₁₋₆ alkylthio group (especially a C₁₋₄ alkylthio group) which issubstituted optionally with a halogen atom such as fluorine and chlorineatoms, etc., such as methylthio; difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthiogroups, etc.);

[0062] (v) an aryl group (for example, a C₆₋₁₄ aryl group such asphenyl, naphthyl, anthryl, phenanthryl groups, etc.);

[0063] (vi) an acyloxy group (for example a C₁₋₃ acyloxy group, etc.such as formyloxy, acetoxy, propionyloxy groups, etc.);

[0064] (vii) a hydroxy group;

[0065] (viii) a nitro group;

[0066] (ix) a cyano group;

[0067] (x) an amino group;

[0068] (xi) a mono- or dialkylamino group (for example, a mono- ordi-C₁₋₆ alkylamino group (especially, mono- or di-C₁₋₄ alkylamino group)such as methylamino, ethylamino, propylamino, dimethylamino,diethylamino groups, etc.);

[0069] (xii) a cyclic amino group (for example, a 5- to 9-memberedcyclic amino group optionally containing, in addition to carbon atoms, 1to 3 heteroatoms such as nitrogen, sulfur and oxygen atoms (for example,pyrrolidino, piperidino, morpholino groups, etc.), etc.;

[0070] (xiii) an acylamino group (for example, a C₁₋₆alkyl-carbonylamino group such as formylamino group, or acetylamino,propionylamino, butyrylamino groups, etc.);

[0071] (xiv) a lower alkyl-substituted carbamoylamino group (such asethylcarbamoylamino group, etc.);

[0072] (xv) an alkylsulfonylamino group (for example, a C₁₋₆alkylsulfonylamino group, etc. such as methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino groups, etc.);

[0073] (xvi) an alkoxycarbonyl group (for example, a C₁₋₆ alkoxycarbonylgroup, etc. such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl groups, etc.);

[0074] (xvii) a carboxyl group;

[0075] (xviii) an alkylcarbonyl group (for example a C₁₋₆alkylcarbonylgroup; etc. such as methyl carbonyl, ethylcarbonyl, butylcarbonylgroups, etc.);

[0076] (xix) a carbamoyl group;

[0077] (xx) amono-ordialkylcarbamoyl group (for example, a mono- ordi-C₁₋₆ alkylcarbamoyl group, etc. such as methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl,dibutylcarbamoyl groups, etc.);

[0078] (xxi) an alkylsulfonyl group (for example, a C₁₋₆ alkylsulfonylgroup, etc. such as methylsulfonyl, ethylsulfonyl, propylsulfonylgroups, etc.);

[0079] (xxii) an oxo group;

[0080] (xxiii) a thioxo group, etc.

[0081] An “optionally substituted alkyl group” means, for example:

[0082] (a) a straight or branched alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, etc.;

[0083] (b) a halogenated C₁₋₆ alkyl group (for example, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl andperfluorobutyl groups, etc.);

[0084] (c) an amino group-substituted C₁₋₆ alkyl group (for example,aminomethyl and 2-aminoethyl groups, etc.);

[0085] (d) amono- or di-C₁₋₆ alkylamino-substituted C₁₋₆ alkyl group(for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyland 2-dimethylaminoethyl groups, etc.);

[0086] (e) a carboxyl group-substituted C₁₋₆ alkyl group (for example,carboxymethyl and carboxyethyl groups, etc.);

[0087] (f) a C₁₋₆ alkoxycarbonyl-substituted C₁₋₆ alkyl group (forexample, methoxycarbonylethyl and ethoxycarbonylethyl groups, etc.);

[0088] (g) a hydroxy group-substituted C₁₋₆ alkyl group (for example,-hydroxymethyl and hydroxyethyl groups, etc.);

[0089] (h) a C₆₋₁₄ aryl group-substituted C₁₋₆alkyl group (for example,benzyl, etc.);

[0090] (i) a C₁₋₆ alkoxy group-substituted C₁₋₆ alkyl group (forexample, methoxymethyl, methoxyethyl, etc.); or,

[0091] (J) a C₇₋₁₅ aralkyloxy group-substitutedC₁₋₆alkyl group (forexample, benzyloxymethyl, etc.), etc.

[0092] A substituent which may be possessed by ring A and ring B may forexample be a halogen atom, an optionally substituted alkyl group, anoptionally halogenated alkoxy group, a mono- or dialkylamino group, anoptionally halogenated alkylthio group, etc.

[0093] A substituent which may be possessed favorably by ring A and ringB includes a halogen atom, an optionally substituted C₁₋₄ alkyl group,an optionally halogenated C₁₋₄ alkoxy group, a mono- or di-C₁₋₄alkylamino group, an optionally halogenated C₁₋₄ alkylthio group, etc.

[0094] Among those listed above, a halogen atom, an optionallysubstituted C₁₋₄ alkyl group and an optionally halogenated C₁₋₄ alkoxygroup are employed preferably.

[0095] A substituent on ring A and ring B may be on any position capableof being substituted on the ring, and when two or more substituents arepresent, they may be same or different and the number of suchsubstituents may be 1 to about 4. The number of the substituents ispreferably 1 to about 3.

[0096] When each of ring A and ring B has a nitrogen atom, a quaternaryammonium salt may be formed together with an anion such as, for example,a halogen ion (such as Cl⁻, Br⁻, I⁻), sulfate ion, hydroxy ion, etc.

[0097] Each of ring A and ring B is preferably an optionally substitutedbenzene ring.

[0098] A substituent on an “optionally substituted benzene” means, forexample, one exemplified above as a substituent on ring A and ring B.

[0099] A condensed ring formed when a substituent on ring A (or ring B)is bound to a position capable of being substituted on ring B (or ringA) and taken together with ring A, ring B and X² described later may forexample be fluorene, anthracene, dibenzofuran, dibenzopyrane,dibenzodioxane, carbazol, acridine, phenothiazine, etc., in detail atricyclic condensed ring represented by Formula:

[0100] wherein each of ring A and ring B has a meaning defined above,and X² has a meaning defined later being preferred.

[0101] One exemplified more preferably is a tricyclic condensed ringrepresented by Formula:

[0102] wherein each of ring A and ring B has a meaning defined above.

[0103] Group “R¹”

[0104] Each R¹ may be same or different and is a hydrogen atom, anoptionally substituted hydrocarbon group, an acyl group, an optionallysubstituted heterocyclic group or SR 2 (wherein R² is a hydrogen atom,an optionally substituted hydrocarbon group, an acyl group or anoptionally substituted heterocyclic group).

[0105] A “hydrocarbon group” in an “optionally substituted hydrocarbongroup” represented by R¹ may for example be an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group and an aryl group, with analkyl group, a cycloalkyl group and an aryl group, especially an alkylgroup, being preferred.

[0106] An “alkyl group” is a straight or branched chain of 1 to 6 carbonatoms, preferably, a straight or branched alkyl group having 1 to 4carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, etc.

[0107] An “alkenyl group” may for example be an alkenyl group having 2to 6 carbon atoms such as ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, sec-butenyl and the like, with an alkenyl group having 2 to4 carbon atoms such as ethenyl, propenyl and isopropenyl being employedpreferably.

[0108] An “alkynyl group” may for example be an alkynyl group having 2to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl,isobutynyl, sec-butynyl and the like, with an alkynyl group having 2 to4 carbon atoms such as ethynyl, propynyl and isopropynyl being employedpreferably.

[0109] A “cycloalkyl group” may for example be a C₃₋₈ cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., with aC₃₋₆ cycloalkyl group such as cyclopropyl and cyclobutyl being employedpreferably.

[0110] An “aryl group” may for example be an aryl group having 6 to 14carbon atoms such as phenyl, naphthyl, anthryl, phenanthryl, etc., withan aryl group having 6 to 10 carbon atoms such as phenyl and naphthylbeing employed preferably.

[0111] A “substituent” on an “optionally substituted hydrocarbon group”may for example be:

[0112] (i) a halogen atom (for example, fluorine, chlorine, bromine,iodine atoms, etc.);

[0113] (ii) an optionally substituted alkyl group;

[0114] (iii) a cycloalkyl group (for example, a C₃₋₈ cycloalkyl group,etc. such as cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.);

[0115] (iv) an optionally substituted aryl group;

[0116] (v) an optionally halogenated alkoxy group (for example, a C₁₋₆alkoxy group, etc. which is substituted optionally with a halogen atomsuch as fluorine and chlorine atoms, ‘etc’, such as methoxy,difluoromethbxy, trichloromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy,isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy groups, C₃₋₈cycloalkyloxy and heterocyclyloxy-groups, etc.);

[0117] (vi) a nitro group;

[0118] (vii) a cyano group;

[0119] (viii) a hydroxy group;

[0120] (ix) an aryloxy group (for example, a C₆₋₁₄ aryloxy group, etc.such as phenoxy and naphthyloxy groups, etc.);

[0121] (x) an aralkyloxy group (for example, a C₆₋₁₄ aryl group C₁₋₄alkyloxy group, etc. such as benzyloxy and phenethyloxy groups, etc.);

[0122] (xi) an optionally halogenated alkylthio group (for example, aC₁₋₆ alkylthio group (especially C₁₋₄ alkylthio group, etc.) which issubstituted optionally with a halogen atom such as fluorine andchlorine, such as methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio groups);

[0123] (xii) an amino group;

[0124] (xiii) an amino group which is mono- or disubstituted by a formylgroup or an optionally substituted alkyl group (for example, a mono- ordi-C₁₋₆ alkylamino group (especially mono- or di-C₁₋₄ alkylamino group)such as methylamino, ethylamino, propylamino, dimethylamino,diethylamino groups, etc., formylamino group, pyrimidinylmethylaminogroup, etc.);

[0125] (xiv) a cyclic amino group (for example, a 5- to 9-memberedcyclic amino group optionally containing 1 to 3 heteroatoms such asoxygen and sulfur atoms in addition to nitrogen atoms (for example,pyrrolidino, piperidino and morpholino groups, etc.);

[0126] (xv) an alkylcarbonylamino group (for example, a C₁₋₆alkylcarbonylamino group, etc. such as acetylamino, propionylamino andbutyrylamino groups, etc.)

[0127] (xvi) an alkoxycarbonylamino group (for example, a C₁₋₆alkoxycarbonylamino group, etc. such as ethoxycarbonylamino group,etc.);

[0128] (xvii) an arylcarbonylamino group (for example, a C₆₋₁₄arylcarbonylamino group, etc. such as benzoylamino group, etc.);

[0129] (xviii) an acyloxy group (for example, a C₁₋₃ acyloxy group, etc.such as formyloxy, acetoxy and propionyloxy groups, etc.);

[0130] (xvix) an aminocarbonyloxy group;

[0131] (xx) a mono- or dialkylaminocarbonyloxy group (for example, amono- or di-C₁₋₆ alkylaminocarbonyloxy group, etc. such asmethylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxyand diethylaminocarbonyloxy groups, etc.);

[0132] (xxi) an alkylsulfonylamino group (for example, a C₁₋₆alkylsulfonylamino group, etc. such as methylsulfonylamino,ethylsulfonylamino and propylsulfonylamino groups, etc.);

[0133] (xxii) an alkoxycarbonyl group (for example, a C₁₋₆alkoxycarbonyl group, etc. such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, etc.);

[0134] (xxiii) an aralkyloxycarbonyl group (for example, a C₇₋₁₅aralkyloxycarbonyl group, etc. such as benzyloxycarbonyl group, etc.);

[0135] (xxiv) an aryloxycarbonyl group (for example a C₆₋₁₄aryloxycarbonyl group, etc. such as phenoxycarbonyl group, etc.);

[0136] (xxv) a carboxyl group;

[0137] (xxvi) an alkylcarbonyl group (for example, a C₁₋₆ alkylcarbonylgroup, etc. such as methylcarbonyl, ethylcarbonyl and butylcarbonylgroups, etc.);

[0138] (xxvii) a cycloalkylcarbonyl group (for example, a C₃₋₈cycloalkylcarbonyl group, etc. such as cyclopentylcarbonyl andcyclohexylcarbonyl groups, etc.);

[0139] (xxviii) an arylcarbonyl group (for example, a C₆₋₁₄ arylcarbonylgroup, etc. such as benzoyl group, etc.);

[0140] (xxix) a carbamoyl group;

[0141] (xxx) a thiocarbamoyl group;

[0142] (xxxi) a mono- or dialkylcarbamoyl group (for example, a mono- ordi-C₁₋₆ alkylcarbamoyl group, etc. such as methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl anddibutylcarbamoyl groups, etc.);

[0143] (xxxii) an alkylsulfonyl group (for example, a C₁₋₆ alkylsulfonylgroup, etc. such as methylsulfonyl, ethylsulfonyl and propylsulfonylgroups, etc.);

[0144] (xxxiii) a cycloalkylsulfonyl group (for example, a C₃₋₈cycloalkylsulfonyl group, etc. such as cyclopentylsulfonyl andcyclohexylsulfonyl groups, etc.);

[0145] (xxxiv) an arylsulfonyl group (for example, a C₆₋₁₄ arylsulfonylgroup, etc. such as phenylsulfonyl and naphthylsulfonyl groups, etc.);

[0146] (xxxv) an aralkylsulfonyl group (for example a C₇₋₁₅aralkylsulfonyl group, etc. such as benzylsulfonyl group, etc.); and,

[0147] (xxxvi) an optionally substituted 5- or 6-membered heterocyclicgroup, etc.

[0148] An “optionally substituted 5- or 6-membered heterocyclic group”as a “substituent” on an “optionally substituted hydrocarbon”represented by R¹ may for example be a 5- or 6-membered aromaticheterocyclic group, a saturated or unsaturated 5- or 6-memberednon-aromatic heterocyclic group, etc.

[0149] Such “5- or 6-membered aromatic heterocyclic group” may forexample be furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pirazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazblyl, 1,3,4-oxyadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl., 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc.

[0150] A “5- or 6-membered non-aromatic heterocyclic group” describedabove may for example be pyrrolidinyl, tetrahydrofuryl,tetrahydrothienyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl and piperazinyl, etc.

[0151] Such non-aromatic heterocyclic group may further be condensedwith other aromatic or non-aromatic homocyclic or heterocyclic rings.

[0152] A “substituent” on an “optionally substituted 5- or 6-memberedheterocyclic group” represented as a “substituent” on an “optionallysubstituted hydrocarbon” may for example be one exemplified as a“substituent” on an “optionally substituted homocyclic or heterocyclicring” represented by ring A and ring B described above.

[0153] In addition, a group represented by formula:

[0154] wherein each symbol has a meaning defined above may also beexemplified as an “optionally substituted hydrocarbon group” representedby R¹.

[0155] The number of the substituents on an “optionally substitutedhydrocarbon group” represented by R¹ is 1 to about 5 (preferably 1 to2), and when two or more substituents are present they may be same ordifferent.

[0156] An “optionally substituted alkyl group” described as a“substituent” on an “optionally substituted hydrocarbon group”represented by R¹ may for example be an “optionally substituted alkylgroup” exemplified as a substituent possessed optionally by a“homocyclic or heterocyclic ring” represented by ring A and ring Bdescribed above.

[0157] An “aryl group” in an “optionally substituted aryl group”described as a “substituent” on an “optionally substituted hydrocarbongroup” represented by R¹ may for example be an aryl group having 6 to 14carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl, etc.,which an aryl having 6 to 10 carbon atoms such as phenyl and naphthylbeing employed preferably.

[0158] A “substituent” on an “optionally substituted aryl group”described as a “substituent” on an “optionally substituted hydrocarbongroup” represented by R¹ may for example be (i) a halogen atom such asfluorine and chlorine, etc., (ii) an optionally halogenated C₁₋₄ alkylgroup such as methyl, ethyl and trifluoromethyl group, etc., or (iii) aC₁₋₄ alkoxy group, etc. su-ch as methoxy and ethoxy groups, etc.

[0159] An “acyl group” represented by R¹ may for example be —(C═O)—R⁶,—SO₂—R⁶, —SO—R⁶, —(C═O)NR⁶R²⁷, —(C═O)O—R⁶ _(C═S)O—R⁶, —(C═S)NR⁶R²⁷,—(P═O)(OR⁶)²-(P═O)(O⁶)(O²⁷ (wherein R⁶ is a hydrogen atom or anoptionally substituted hydrocarbon group, an optionally substitutedamino group or an optionally substituted hydroxy group, and R²⁷ is ahydrogen atom or a lower alkyl group (for example, a C₁₋₆ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl, etc., with a C₁₋₃ alkyl group such asmethyl, ethyl, propyl and isopropyl, etc. being preferred)), etc.

[0160] An “optionally substituted hydrocarbon group” represented by R⁶may for example be one exemplified as an “optionally substitutedhydrocarbon group” represented by R¹ described above.

[0161] A “substituent” on an “optionally substituted amino group”represented by R⁶ may for example be an optionally substitutedhydrocarbon group, an optionally substituted hydroxy group and an acylgroup, etc.

[0162] An “optionally substituted hydrocarbon group” as a “substituent”on an “optionally substituted amino group represented by R may forexample be one exemplified as an “optionally substituted hydrocarbongroup” represented by R¹ described above.

[0163] An “optionally substituted hydroxy group” as a “substituent” onan “optionally substituted amino group” represented by R⁶ may forexample be (i) a hydroxy group, (ii) a C₁₋₆ alkoxy group (for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy groups, etc.),(iii) a C₆₋₁₄ aryloxy group (for example, phenyloxy and naphthyloxygroups, etc.), (iv) a C₁₋₆ alkylcarbonyloxy group (for example,formyloxy, acetoxy and propionyloxy groups, etc.), and (v) a C₆₋₁₄arylcarbonyloxy group (for example, benzyloxy and naphthylcarbonyloxygroups, etc.), etc., with a hydroxy group and a C₁₋₆ alkoxy group (forexample, methoxy, ethoxy, propoxy and isopropoxy groups, etc.) beingpreferred.

[0164] An “acyl group” as a “substituent” on an “optionally substitutedamino group” represented by R may for example be —(C═O)—R²⁸, —SO₂—R²⁸,—SO—R²⁸—(C═O)NR²⁸R²⁹, —(C═O)O—R²⁸, —(C═S)O—R²⁸, —(C═S)NR²⁸R²⁹(wherein Ris a hydrogen atom or an optionally substituted hydrocarbon group, andR²⁹ is a hydrogen atom or a lower alkyl group (for example, a C₁₋₆ alkylgroup, etc. such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl and hexyl, etc., with a C₁₋₃ alkyl groupsuch as methyl, ethyl, propyl and isopropyl, etc. being preferred)),etc.

[0165] An “optionally substituted hydrocarbon group” represented by Rmay for example be one exemplified as an “optionally substitutedhydrocarbon group” represented by R¹ described above.

[0166] Each of “C₁₋₆ alkoxy group”, “C₆₋₁₄ aryloxy group”, “C₁₋₆alkylcarbonyloxy group” and “C₆₋₁₄ arylcarbonyloxy group” exemplified asan “optionally substituted hydroxy group” as a “substituent” on an“optionally substituted amino group” represented by R⁶ may further besubstituted by one similar to a “substituent” on an “optionallysubstituted hydrocarbon group” represented by R¹ described above, andsuch substituent is preferably a halogen atom (for example, fluorine,chlorine and bromine, etc.).

[0167] An “optionally substituted hydroxy group” represented by R⁶described above may for example be one exemplified as an “optionallysubstituted hydroxy group” as a “substituent” on an “optionallysubstituted amino group” represented by R⁶ described above.

[0168] Otherwise, R⁶ and R²⁷ may be taken together to form a cyclicamino group (for example, a 5- to 9-membered cyclic amino group whichmay contain 1 to 3 heteroatoms such as oxygen and sulfur atoms inaddition to nitrogen atoms (for example, pyrrolidino, piperidino andmorpholino groups, etc.), etc.).

[0169] A “heterocyclic group” in an “optionally substituted heterocyclicgroup” represented by R¹ may for example be an aromatic heterocyclicgroup, a saturated or unsaturated non-aromatic heterocyclic groupcontaining as an ring member atom (ring atom), in addition to carbonatoms, at least one (preferably 1 to 4, more preferably 1 to 2) atom of1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms.

[0170] Such “aromatic heterocyclic group” may for example be 5- or6-membered aromatic monocyclic heterocyclic group such as an aromaticmonocyclic heterocylic group (for example, furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxkadiazblyl, 1,2,4-oxadiazolyl; 1,3,4-oxadiazblyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl, etc.), etc. and a 8- to12-membered aromatic condensed heterocyclic group such as an aromaticcondensed heterocyclic group (for example, benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, sinnolynyl, quinazolyl, quinoxanyl, phthalazinyl,naphthylidinyl, purinyl, pteridinyl, carbazolyl, α-carborynyl,β-carborynyl, γ-carborynyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiynyl, thianthrenyl, phenanthridinyl,phenanthronyl, indolydinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl, etc.)(preferably, a heterocyclic ring formed by condensing a 5- or 6-memberedaromatic monocyclic heterocyclic group described above with a benzenering, or a heterocyclic ring formed by condensing same or different 2heterocyclic rings of 5- or 6-membered aromatic monocyclic heterocyclicgroups described above).

[0171] A “non-aromatic heterocyclic group” described above may forexample be a 3- to 8-membered (preferably 5- to 6-membered) saturated orunsaturated (preferably saturated) non-aromatic heterocyclic group, etc.such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl and piperazinyl.

[0172] A “substituent” on an “optionally substituted heterocyclic group”represented by R¹ may for example be one exemplified as a substituentwhich may be possessed by a “homocyclic or heterocyclic ring”represented by ring A and ring B, as well as a group represented by Y (Yhas a meaning defined above) in Formula (I) shown above and a grouprepresented by Formula:

[0173] wherein each symbol has a meaning defined above.

[0174] A “substituent” on an “optionally substituted heterocyclic group”represented by R1 may be on any position capable of being substituted ona ring, and when two or more substituents are present then they may besame or different and the number of them may be 1 to about 3. The numberof the substituents is preferably 1 to about 2.

[0175] An “optionally substituted hydrocarbon group” represented by R²in “SR² (wherein R is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group)” represented by R¹ may for example be oneexemplified as an “optionally substituted hydrocarbon group” representedby R¹ described above.

[0176] An “acyl group” represented by R² in “SR² (wherein R² is ahydrogen atom, an optionally substituted hydrocarbon group, an acylgroup or an optionally substituted heterocyclic group)” represented byR¹ may for example be one exemplified as an “acyl group” represented byR¹ described above.

[0177] An “optionally substituted heterocyclic group” represented by R²in “SR² (wherein R² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group)” represented by R¹ may for example be oneexemplified as an “optionally substituted heterocyclic group”represented by R¹ described above.

[0178] Those employed preferably as R¹ may for example be a hydrogenatom, an optionally substituted lower alkyl group, —(C═O)—R⁶ (wherein R⁶has a meaning defined above) or SR² (wherein R² has a meaning definedabove).

[0179] An “optionally substituted lower alkyl group” as a preferredexample of R¹ may for example be:

[0180] (a) a straight or branched alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl;

[0181] (b) a halogenated C₁₋₆ alkyl group (for example, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl andperfluorobutyl groups, etc.);

[0182] (c) an amino group-substituted C₁₋₆ alkyl group (for example,aminomethyl and 2-aminoethyl groups, etc.);

[0183] (d) a mono- or di-C₁₋₆ alkylamino group-substituted C₁₋₆ alkylgroup (for example, methylaminomethyl, dimethylaminomethyl,2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);

[0184] (e) a carboxyl group-substituted C₁₋₆ alkyl group (for example,carboxymethyl and carboxyethyl groups, etc.);

[0185] (f) a C₁₋₆ alkoxycarbonyl group-substituted C₁₋₆ alkyl group (forexample, methoxycarbonylethyl, ethoxycarbonylethyl andt-butoxycarbonylmethyl groups, etc.);

[0186] (g) a hydroxy group-substituted C₁₋₆ alkyl group (for example,hydroxymethyl and hydroxyethyl groups, etc.);

[0187] (h) a C₆₋₁₄ aryl group-substituted C₁₋₆ alkyl group (for example,benzyl, etc.);

[0188] (i) a C₁₋₆ alkoxy group-substituted C₁₋₆ alkyl group (forexample, methoxymethyl, methoxyethyl, etc.); or,

[0189] (j) a C₇₋₁₅ aralkyloxy group-substituted C₁₋₆ alkyl group (forexample, benzyloxymethyl, etc.), etc.

[0190] More preferably, R¹ is (1) a hydrogen atom; (2) a C₁₋₆ alkylgroup substituted optionally with [1] a C₁₋₆ alkoxycarbonyl group(especially, ethoxycarbonyl, t-butoxycarbonyl, etc.), or with [2] aC₆₋₁₄ aryl group (especially phenyl, etc.), or, (3) —(C═O)—R^(6a)(wherein R^(6a) is a C₁₋₆ alkyl group (especially methyl, etc.) or aC₆₋₁₄ aryl group (especially phenyl, etc.), etc.), etc.

[0191] Furthermore, a group represented by Formula:

[0192] wherein each symbol has a meaning defined above, or by Formula:

[0193] wherein each symbol has a meaning defined above may also bementioned to be preferable as R¹.

[0194] Group “X¹”

[0195] X¹ is a bond, an optionally substituted divalent C₁₋₃ aliphatichydrocarbon group or —NR³— (wherein R³ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an acyl group).

[0196] A “divalent C₁₋₃ aliphatic hydrocarbon group” in an “optionallysubstituted divalent C₁₋₃ aliphatic hydrocarbon group” is a groupobtained by removing (2 in total of) hydrogen atoms each one of which isbinding to a same or different carbon atoms in a saturated orunsaturated C₁₋₃ aliphatic hydrocarbon. Those exemplified typically are:

[0197] (i) a C₁₋₃ alkylene group (for example, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH(CH₃)—CH₂—, etc.);

[0198] (ii) a C₂₋₃-alkenylene group (for example —CH═CH—, —CH═CH—CH₂—,etc.);

[0199] (iii) a C₂₋₃ alkynylene group (for example,

[0200] etc.).

[0201] Among those listed above, a C₁₋₃ alkylene group (for example,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— or —CH(CH₃)—CH₂—, etc.) are employedfrequently. Preferably, —CH₂— is employed.

[0202] A “substituent” on an “optionally substituted divalent C₁₃aliphatic hydrocarbon group” represented by X¹ may for example be oneexemplified as a “substituent” on an “optionally substituted hydrocarbongroup” represented by R¹ described above (provided that a grouprepresented by Formula:

[0203] wherein each symbol has a meaning defined above as a substituenton an optionally substituted hydrocarbon group represented by R¹ isexcluded from the substituents on an “optionally substituted divalentC₁₋₃ aliphatic hydrocarbon group”), as well as an oxo group and a thioxogroup, etc.

[0204] An “optionally substituted hydrocarbon group” represented by “R³”in “—NR³-” represented by X¹ may for example be one exemplified as an“optionally substituted hydrocarbon group” represented by R¹ describedabove (provided that a group represented by Formula:

[0205] wherein each symbol has a meaning defined above as a substituenton a hydrocarbon group represented by R¹ is excluded from thesubstituents on a hydrocarbon group represented by R¹).

[0206] An “acyl group” represented by “R³” in “—NR³—” represented by X¹may for example be one exemplified as an “acyl group” represented by R¹described above.

[0207] X¹ is preferably an optionally substituted methylene group. A“substituent” on such “optionally substituted methylene group” may forexample be one exemplified as a “substituent” on an “optionallysubstituted divalent C₁₃ aliphatic hydrocarbon group” represented by X¹.

[0208] A particularly preferred X¹ is an unsubstituted methylene group.

[0209] Group “X²”

[0210] X² is a bond, an optionally substituted divalent C₁₋₃ aliphatichydrocarbon group, —NR⁴— (wherein R⁴ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an acyl group), —O— or —S(O)_(p)—(wherein p is 0, 1 or 2).

[0211] An “optionally substituted divalent C₁₋₃ aliphatic hydrocarbongroup” represented by X² may for example be one exemplified as an“optionally substituted divalent C₁₃ aliphatic hydrocarbon group”represented by X¹ described above.

[0212] An “acyl group” represented by “R⁴” in “—NR⁴-” represented by X²may for example be one exemplified as an “acyl group” represented by R¹described above.

[0213] X² is preferably —O—.

[0214] Group “Y”

[0215] Each Y may be same or different and is a hydrogen atom, anoptionally substituted hydrocarbon group, a halogen atom, a carboxylgroup, an acyl group, an optionally substituted hydroxy group, anoptionally substituted amino group, SR⁵ (wherein R⁵ is a hydrogen atom,an optionally substituted hydrocarbon group, an acyl group or anoptionally substituted heterocyclic group) an oxo group, a thioxo group,an optionally substituted imino group, a nitro group or a cyano group.

[0216] An “optionally substituted hydrocarbon group” represented by Ymay for example be one exemplified as an “optionally substitutedhydrocarbon group” represented by R³ described above.

[0217] A “halogen atom” represented by Y may for example be fluorine,chlorine, bromine, iodine, etc.

[0218] An “acyl group” represented by Y may for example be oneexemplified as an “acyl group” represented by R¹ described above.

[0219] An “optionally substituted hydroxy group” represented by Y mayfor example be one exemplified as an “optionally substituted hydroxygroup” as a “substituent” on an “optionally substituted amino group”represented by R⁶-described-above.

[0220] An “optionally substituted amino group” represented by Y may forexample be one exemplified as an “optionally substituted amino group”represented by R⁶ described above.

[0221] An “optionally substituted hydrocarbon group” as “R⁵, in “SR⁵”represented by Y may for example be one exemplified as an “optionallysubstituted hydrocarbon group” represented by R³ described above.

[0222] An “acyl group” as “R⁵” in “SR⁵” represented by Y may for examplebe one exemplified as an “acyl group” represented by R¹ described above.

[0223] An “optionally substituted heterocyclic group” as “R⁵” in “SR⁵”represented by Y may for example be one exemplified as an “optionallysubstituted heterocyclic group” represented by R¹ described above(provided that, among the examples of a “substituent” in an “optionallysubstituted heterocyclic group” represented by R¹ described above, agroup represented by Y (wherein Y has a meaning defined above) and agroup represented by Formula:

[0224] wherein each symbol has a meaning defined above are excluded fromthe substituents on an “optionally substituted heterocyclic group”represented by R⁵).

[0225] A substituent on an “optionally substituted imino group”represented by Y may for example be one exemplified as an “optionallysubstituted hydrocarbon group” or an “acyl group” represented by R⁴.

[0226] Those employed preferably as Y may for example be a hydrogenatom, an optionally substituted lower alkyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, SR¹²(wherein R¹² is a hydrogen atom, an optionally substituted hydrocarbongroup, an acyl group or an optionally substituted heterocyclic group) oran oxo group, etc.

[0227] An “optionally substituted lower alkyl group” described above asa preferred example of Y may for example be:

[0228] (a) a straight or branched alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, etc.;

[0229] (b) a halogenated C₁₋₆ alkyl group (for example, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl andperfluorobutyl groups, etc.);

[0230] (c) an amino group-substituted C₁₋₆ alkyl group (for example,aminomethyl and 2-aminoethyl groups, etc.);

[0231] (d) a mono- or di-C₁₋₆ alkylamino group-substituted C₁₋₆ alkylgroup (for example, methylaminomethyl, dimethylaminomethyl,2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);

[0232] (e) a carboxyl group-substituted C₁₋₆ alkyl group (for example,carboxymethyl and carboxyethyl groups, etc.);

[0233] (f) a C₁₋₆ alkoxycarbonyl group-substituted C₁₋₆ alkyl group (forexample, methoxycarbonylethyl, ethoxycarbonylethyl andt-butoxycarbonylmethyl groups);

[0234] (g) a hydroxy group-substituted C₁₋₆ alkyl group (for example,hydroxymethyl and hydroxyethyl groups, etc.);

[0235] (h) a C₆₋₁₄ aryl group-substituted C₁₋₆ alkyl group (for example,benzyl, etc.);

[0236] (i) a C₁₋₆ alkoxy group-substituted C₁₋₆ alkyl group (forexample, methoxymethyl, methoxyethyl, etc.); or,

[0237] (j) a C₇₋₁₅ aralkyloxy group-substituted C₁₋₆ alkyl group (forexample, benzyloxymethyl, etc.), etc.

[0238] An “optionally substituted hydroxy group” described above as apreferred example of Y may for example be one exemplified as an“optionally substituted hydroxy group” as a “substituent” on an“optionally substituted amino group” represented by R⁶ described above.

[0239] An “optional substituted amino group” described above as apreferred example of Y may for example be one exemplified as an“optionally substituted amino group” represented by R⁶ described above.

[0240] An “optionally substituted hydrocarbon group” as “R¹²” in “SR¹²”described above as a preferred example of Y may for example be oneexemplified as an “optionally substituted hydrocarbon group” representedby R³ described above.

[0241] An “acyl group” as “R¹²” in “SR¹²” represented as Y may forexample be one exemplified as an “acyl group” represented by R¹described above.

[0242] An “optionally substituted heterocyclic group” as “R¹²” in “SR¹²”represented by Y may for example be one exemplified as an “optionallysubstituted heterocyclic group” represented by R¹ described above(provided that among the examples of a “substituent” in an “optionallysubstituted heterocyclic group” represented by R¹ described above, agroup represented by Y (wherein Y has a meaning defined above) and agroup represented by Formula:

[0243] wherein each symbol has a meaning defined above are excluded fromthe substituents on an “optionally substituted heterocyclic group”represented by R¹²).

[0244] More preferably, Y may for example be an unsubstituted C₁₋₆ alkylgroup (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, etc.), a hydroxy group-substituted C₁₋₆ alkylgroup (for example, hydroxymethyl and hydroxyethyl groups, etc.), analkoxy group-substituted C₁₋₆ alkyl group (for example, benzyloxymethyland methoxymethyl groups, etc.) as well as an oxo group.

[0245] Number “m”

[0246] Each m may be same or different and is 0 or 1. m is preferably 0.

[0247] Number “n”

[0248] Each n is an integer of 1 to 3. n is preferably 1 to 2,especially 1.

[0249] Numbers “q₁ and q₂”

[0250] q₁ is an integer of 1 to 2n+4, q₂ is an integer of 0 to 2n+3, andthe sum of q₁ and q₂ is 2n+4.

[0251] Preferably q₁ is 1.

[0252] Partial Structure of Compound Represented by Formula [I]

[0253] A preferred group represented by Formula:

[0254] which is a partial structure of Formula [I] shown above may forexample be a group represented by Formula:

[0255] wherein each of R⁷ to R¹¹ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹² (wherein R¹² has a meaning defined above) and each ofother symbols has a meaning defined above.

[0256] An “optionally substituted lower alkyl group” represented by eachof R⁷ to R¹¹ may for example be:

[0257] (a) a straight or branched alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, etc.;

[0258] (b) a halogenated C₁₋₆ alkyl group (for example, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl andperfluorobutyl groups, etc.);

[0259] (c) an amino group-substituted C₁₋₆ alkyl group (for example,aminomethyl and 2-aminoethyl groups, etc.);

[0260] (d) a mono- or di-C₁₋₆ alkylamino group-substituted C₁₋₆ alkylgroup (for example, methylaminomethyl, dimethylaminomethyl,2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);

[0261] (e) a carboxyl group-substituted C₁₋₆ alkyl group (for example,carboxymethyl and carboxyethyl groups, etc.);

[0262] (f) a C₁₋₆ alkoxycarbonyl group-substituted C₁₋₆ alkyl group (forexample, methoxycarbonylethyl, ethoxycarbonylethyl andt-butoxycarbonylmethyl groups, etc.);

[0263] (g) a hydroxy group-substituted C₁₋₆ alkyl group (for example,hydroxymethyl and hydroxyethyl groups, etc.);

[0264] (h) a C₆₋₁₄ aryl group-substituted C₁₋₆ alkyl group (for example,benzyl, etc.);

[0265] (i) a C₁₋₆ alkoxy group-substituted C₁₋₆ alkyl group (forexample, methoxymethyl, methoxyethyl, etc.); or,

[0266] (j) a C₇₋₁₅ aralkyloxy group-substituted C₁₋₆ alkyl group (forexample, benzyloxymethyl, etc.), etc.

[0267] An “optionally substituted hydroxy group” represented by each ofR⁷ to R¹¹ may for example be one exemplified as an “optionallysubstituted hydroxy group” as a “substituent” on an “optionallysubstituted amino group” represented by R⁶ described above.

[0268] An “optionally substituted amino group” represented by each of R⁷to R¹¹ may for example be one exemplified as an “optionally substitutedamino group” represented by R⁶ described above.

[0269] More preferably, each of R⁷ to R” may for example be anunsubstituted C₁₋₆ alkyl group (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl), a hydroxygroup-substituted C₁₋₆ alkyl group (for example, hydroxymethyl andhydroxyethyl groups, etc.), an alkoxy group-substituted C₁₋₆ alkyl group(for example, benzyloxymethyl and methoxymethyl groups, etc.) as well asan oxo group.

[0270] A most preferred group represented by Formula

[0271] which is a partial structure of Formula [I] shown above may forexample be a group represented by Formula:

[0272] wherein each of R¹³ to R²⁵ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹²

[0273] (wherein R¹² has a meaning defined above).

[0274] An “optionally substituted lower alkyl group” represented by eachof R¹³ to R²⁵ may for example be:

[0275] (a) a straight or branched alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, etc.;

[0276] (b) a halogenatedC₁₋₆alkyl group (for example, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl,2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl andperfluorobutyl groups, etc.);

[0277] (c) an amino group-substitutedC₁₋₆alkyl group (for example,aminomethyl and 2-aminoethyl groups, etc.);

[0278] (d) a mono- or di-C₁₋₆ alkylamino group-substituted C₁₋₆ alkylgroup (for example, methylaminomethyl, dimethylaminomethyl,2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.);

[0279] (e) a carboxyl group-substituted C₁₋₆ alkyl group (for example,carboxymethyl and carboxyethyl groups, etc.);

[0280] (f) a C₁₋₆ alkoxycarbonyl group-substituted C₁₋₆ alkyl group (forexample, methoxycarbonylethyl, ethoxycarbonylethyl andt-butoxycarbonylmethyl groups, etc.);

[0281] (g) ahydroxy group-substituted C₁₋₆ alkyl group (for example,hydroxymethyl and hydroxyethyl groups, etc.);

[0282] (h) a C₆₋₁₄ aryl group-substituted C₁₋₆ alkyl group (for example,benzyl, etc.);

[0283] (i) a C₁₋₆ alkoxy group-substituted C₁₋₆ alkyl group (forexample, methoxymethyl, methoxyethyl, etc.); or,

[0284] (j) a C₇₋₁₅ aralkyloxy group-substituted C₁₋₆ alkyl group (forexample, benzyloxymethyl, etc.), etc.

[0285] An “optionally substituted hydroxy group” represented by each ofR¹³ to R²⁵ may for example be one exemplified as an “optionallysubstituted hydroxy group” as a “substituent” on an “optionallysubstituted amino group” represented by R described above.

[0286] An “optionally substituted amino group” represented by each ofR¹³ to R²⁵ may for example be one exemplified as an “optionallysubstituted amino group” represented by R⁶ described above.

[0287] More preferably, each of R¹³ to R²⁵ may for example be anunsubstituted C₁₋₆ alkyl group (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), a hydroxygroup-substituted C₁₋₆ alkyl group (for example, hydroxymethyl andhydroxyethyl groups, etc.), an alkoxy group-substituted C₁₋₆ alkyl group(for example, benzyloxymethyl and methoxymethyl groups, etc.) as well asan oxo group.

[0288] Among the groups represented by Formula:

[0289] wherein each symbol has a meaning defined above, each of which isexemplified as a preferred group represented by Formula:

[0290] which is a partial structure of Formula [I] shown above, onepreferred particularly may for example be a group represented byFormula:

[0291] wherein each symbol has a meaning defined above.

[0292] Preferred examples of a compound represented by Formula [I] mayfor example be the compounds represented later by Formulae [Ia], [Ib],[Ic], [Id], [Ie], [If], [Ig], [Ih], [Ii], [XXXIV] and [XXXVII].

[0293] One preferred particularly is a compound represented by Formula[I] wherein both of ring A and ring B are benzene rings, R¹ is an acylgroup, X¹ is methylene, X² is an oxygen atom and n is 1.

[0294] Optical Isomers of Compound Represented by Formula [I]

[0295] While a compound represented by Formula [I] or a salt thereof canexist as an optical isomer when it contains an asymmetric carbon in itsstructure, a preferable optical isomer may for example be a compoundrepresented by Formula:

[0296] wherein each symbol has a meaning defined above or a saltthereof.

[0297] A method for producing compound (I) according to the invention ora salt thereof is discussed below.

[0298] Compound (I) according to the invention or a salt thereof can beproduced by methods (A) to (N) described below.

[0299] (Method A) A Compound Represented by Formula:

[0300] wherein q_(1a) is an integer of 1 to 2n+2, q_(2a) is an integerof 0 to 2n+1, and the sum of q_(1a) and q_(2a) is 2n+2 and each of othersymbols has a meaning defined above which is encompassed within compound(I) of the invention or a salt thereof can be produced for example byreacting a compound represented by Formula:

[0301] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0302] wherein q_(1a) is an integer of 1 to 2n+2, q_(2a) is an integerof 0 to 2n+1, and the sum of q_(1a) and q_(2a) is 2n+2 or a salt thereofor with a compound represented by Formula:

[0303] wherein each symbol has a meaning defined above or a saltthereof.

[0304] In this reaction, one mole of compound [II] or a salt thereof isreacted usually with 1 to 5 moles, preferably 1 to 3 moles of compound[III] or a salt thereof or compound [IV] or a salt thereof.

[0305] A reaction solvent is an aromatic hydrocarbon such as benzene,toluene and xylene, etc., an organic acid such as acetic acid, etc., anorganic acid anhydride such as acetic anhydride, etc. and an amide suchas N,N-dimethylformamide and N,N-dimethylacetamide, etc.

[0306] This reaction is conducted usually under a dehydrating condition.The addition of an acid in this reaction allows the reaction to proceedadvantageously. Such acid is preferably an inorganic acid such ashydrochloric acid and sulfuric acid, etc. and an organic acid such asmethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalicacid, fumaric acid and maleic acid, etc. While the amount of an acidemployed may vary depending on the types of the compound and the solventemployed as well as other reaction conditions, it is usually 0.01 to 1mole, preferably 0.05 to 0.1 mole per 1 mole of the compound.

[0307] The reaction temperature is usually 0 to 20° C., preferably 50 to150° C.

[0308] The reaction time is usually 30 minutes to 48 hours, preferably 1to 24 hours.

[0309] Compound [II] is produced for example by method N describedbelow, and compound [III] or [IV] is commercially available or may be asulfur-substituted acid anhydride and a dicarboxylic acid produced forexample in method D described below.

[0310] (Method B) Compound (I) or a salt thereof according to theinvention can be produced for example by reacting a compound representedby Formula:

[0311] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0312] wherein each symbol has a meaning defined above or a salt thereofor with a compound represented by Formula:

[0313] wherein each symbol has a meaning defined above or a salt thereofto produce a compound represented by Formula:

[0314] wherein each symbol has a meaning defined above or a salt thereofor a compound represented by Formula:

[0315] wherein each symbol has a meaning defined above or a saltthereof, followed by reacting a compound represented by Formula [VII] or[VIII] shown above or a salt thereof with a compound represented by R¹SH(wherein R¹ has a meaning defined above) or a salt thereof.

[0316] In order to react a compound represented by Formula [II] or asalt thereof with a compound represented by Formula [V] or [VI] or asalt thereof to form a compound represented by Formula [VII] or [VIII]orasalt thereof, a method similar to (method A) described above may beemployed.

[0317] In a reaction to produce a compound represented by Formula [I] ora salt thereof from a compound represented by Formula [VII] or [VIII] ora salt thereof, 1 to 5 moles, preferably 1 to 3 moles of a compoundrepresented by R¹SH (wherein R¹ has a meaning defined above) is used per1 mole of a compound represented by Formula [VII) or [VIII] or a saltthereof.

[0318] R¹SH may for example be an inorganic sulfide such as hydrogensulfide, sodium hydrogen sulfide and sodium sulfide, etc. and theirsalts, an organic sulfur-containing acid such as thioacetic acid andthiobenzoic acid, etc. and their salts, an aliphatic mercaptan such asmethylmercaptan, benzylmercaptan, triphenylmethylmercaptan and3-mercaptopropionic acid derivatives, etc., an aromatic mercaptan suchas thiophenol and a thiourea.

[0319] A reaction solvent is an alcohol such as methanol and ethanol,etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatichydrocarbon such as benzene, toluene and xylene, etc., an ester such asethyl acetate, etc., a halogenated hydrocarbon such as chloroform anddichloromethane, etc., a nitrile such as acetonitrile, etc., an amidesuch as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and asulfoxide such as dimethylsulfoxide, etc.

[0320] The addition of a base in this reaction allows the reaction toproceed advantageously. Such base is an inorganic base (alkaline metalhydroxide such as sodium hydroxide and potassium hydroxide, etc.,alkaline metal hydrogen carbonate such as sodium hydrogen carbonate andpotassium hydrogen carbonate, etc., alkaline metal carbonate such assodium carbonate and potassium carbonate, etc., alkaline metal hydridesuch as sodium hydride and potassium hydride, etc., sodium amide,alkoxide such as sodium methoxide and sodium ethoxide, etc.) and anorganic base (amine such as trimethylamine, triethylamine anddiisopropylethylamine, cyclic amine such as pyridine, etc.), etc.

[0321] Instead of using a base in this reaction, a compound representedby R¹SH (wherein R¹ has a meaning defined above) or a salt thereof maybe converted for example into an alkaline metal salt or an alkalineearth metal salt, which may then be reacted with a compound representedby Formula [VII] or [VIII] or a salt thereof.

[0322] While the amount of a base employed may vary depending on thetypes of the compound and the solvent employed as well as other reactionconditions, it is usually 1 to 10 moles, preferably 1 to 5 moles per 1mole of a compound represented by R¹SH (wherein R¹ has a meaning definedabove) or a salt thereof. The reaction temperature is usually −50 to200° C., preferably −20 to 100° C. The reaction time may vary dependingon the type of the compound and the reaction temperature, and is usually1 to 72 hours, preferably 1 to 24 hours.

[0323] (Method C) A Compound Represented by Formula:

[0324] wherein q_(2b) is 2n+3 and each of other symbols has a meaningdefined above which is encompassed within compound (I) of the inventionor a salt thereof can be produced for example by reacting a compoundrepresented by Formula:

[0325] wherein each symbol has a meaning defined above or a salt thereofwith an oxidizing agent.

[0326] An oxidizing agent employed in this reaction may be an ordinarydisulfide bond-forming reagent found in “SHINJIKKENKAGAKUKOZA”, Vol.15,Oxidation and Reduction (MARUZEN), for example, a halogen such aschlorine, bromine and iodine, etc., an N-halogen carboxylimide such asN-chlorosuccinimide, etc. or a sulfonamide, a metallic oxidizer such asa chromic acid, lead tetraacetate, potassium permanganate and ironchloride, etc., an organic peroxide such as m-chloroperbenzoic acid andperacetic acid, etc. or hydrogen peroxide or an air oxidation, etc.

[0327] In this reaction, usually 1 to 5 moles, preferably 1 to 2 molesof an oxidizing agent is employed per 1 mole of compound [IX] or a saltthereof.

[0328] A reaction solvent is an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc.

[0329] The addition of a base in this reaction allows the reaction toproceed advantageously. Such base is an inorganic base (alkaline metalhydroxide such as sodium hydroxide and potassium hydroxide, etc.,alkaline metal hydrogen carbonate such as sodium hydrogen carbonate andpotassium hydrogen carbonate, etc., alkaline metal carbonate such assodium carbonate and potassium carbonate, etc., halide such as sodiumiodide and potassium iodide, etc., alkaline metal hydride such as sodiumhydride and potassium hydride, etc., sodium amide, alkoxide such assodium methoxide and sodium ethoxide, etc.) and an organic base (aminesuch as trimethylamine, triethylamine and diisopropylethylamine, etc.,cyclic amine such as pyridine, etc.). While the amount of a baseemployed may vary depending on the types of the compound and the solventemployed as well as other reaction conditions, it is usually 0.1 to 20moles, preferably 1 to 2 moles per 1 mole of compound [IX] or a saltthereof.

[0330] The reaction temperature is usually −20 to 200° C., preferably 0to 100° C. The reaction time is usually 1 minute to 24 hours, preferably1 minute to 5 hours.

[0331] (Method D) A compound represented by Formula:

[0332] wherein q_(1c) is an integer of 1 to 2n+2, q_(2c) is an integerof 0 to 2n+1, and the sum of q_(1c), and q_(2c) is 2n+2 which isencompassed within compound (I) of the invention or a salt thereof canbe produced for example by reacting a compound represented by Formula:

[0333] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0334] wherein each symbol has a meaning defined above or a saltthereof.

[0335] In this reaction, compound [X] or a salt thereof is first reactedwith various acid anhydrides or acid halides to form a correspondingacid anhydride. A reagent employed is an acid anhydride or an acidhalide of an ordinary organic acid such as acetic acid and benzoic acid,etc.

[0336] This reaction employs 1 to 50 moles of a reagent per 1 mole ofcompound [X] or a salt thereof. While the reaction solvent is anaromatic hydrocarbon such as benzene, toluene and xylene, etc., anorganic acid such as acetic acid, etc., a nitrile such as acetonitrile,etc. and an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc., it may be an acid anhydride itself employedas a reagent. While the reaction temperature may vary depending oncompound [X] or a salt thereof employed as well as other reactionconditions, it is 0 to 200° C., preferably 20 to 150° C. The reactiontime is 30 minutes to 24 hours, preferably 1 to 10 hours. An acidanhydride thus obtained and compound [II] or a salt thereof aresubjected to a method similar to that in (Method A) described above toproduce compound [Ic] or a salt thereof.

[0337] Among compounds represented as compounds [Ic], one wherein R¹ isother than an acyl group can be hydrolyzed with an acid or a base toproduce a compound wherein R¹ is H.

[0338] An acid which may be employed may for example be an inorganicacid such as hydrochloric acid, sulfuric acid and nitric acid, etc., anda base may for example be an alkaline metal hydroxide such as sodiumhydroxide and potassium hydroxide, etc., an alkaline metal hydrogencarbonate such as sodium hydrogen carbonate and potassium hydrogencarbonate, etc., an alkaline metal carbonate such as sodium carbonateand potassium carbonate, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., ammonia, an organic amine such asmethylamine and ethylamine, etc.

[0339] This reaction is conducted in a 20 to 50 volumes of an aqueoussolution of an inorganic acid described above (usually at 10 to 30%) per1 g of a compound among compounds [Ic] wherein R¹ is an acyl group, orin an aqueous solution containing 3 to 10 moles of a base describedabove per 1 mole of a compound among compounds [Ic] wherein R¹ is anacyl group. In view of the solubility of a compound, the reaction may beperformed in an aqueous solution described above which is supplementedwith an organic solvent, or the reaction may be performed in an organicsolvent. An organic solvent which may be employed is an alcohol such asmethanol and ethanol, etc., an organic acid such as acetic acid, etc.,an ether such as dioxane and tetrahydrofuran, etc., a nitrile such asacetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc.

[0340] While the reaction temperature may vary depending on the compoundamong compounds [Ic] wherein R¹ is an acyl group as well as otherconditions, it is usually 0 to 200° C., preferably 20 to 150° C. Thereaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.

[0341] Alternatively, a compound represented by Formula (X) shown aboveor a salt thereof can be produced also by reacting a compoundrepresented by Formula:

[0342] wherein L¹ is a leaving group, each R^(a) may be same ordifferent and is an optionally substituted hydrocarbon group, and Y hasa meaning defined above or a salt thereof with a sulfur-containingnucleophilic agent followed by a hydrolysis.

[0343] A leaving group represented by L¹ in compound [XI] may forexample be hydroxy, a halogen atom (for example, chlorine, bromine andiodine, etc.), a substituted sulfonyloxy (for example,methanesulfonyloxy and p-toluenesulfonyloxy, etc.), an acyloxy (such asacetoxy and benzoyloxy, etc.), and an oxy group substituted by aheterocyclic ring or an aryl group (such as succinimide, benzotriazole,quinoline and 4-nitrophenyl, etc.).

[0344] An optionally substituted hydrocarbon group represented by R⁶ mayfor example be one exemplified as an “optionally substituted hydrocarbongroup” represented by R¹ described above, with a C₁₋₄ alkyl group suchas methyl, ethyl and propyl, etc. being employed preferably.

[0345] A sulfur-containing nucleophilic agent is an inorganic sulfidesuch as hydrogen sulfide, sodium hydrogen sulfide and sodium sulfide,etc., an organic sulfur-containing acid such as thioacetic acid andthiobenzoic acid, etc. as well as their salts, a mercaptan such asbenzylmercaptan, triphenylmethylmercaptan and 3-mercaptopropionic acidderivatives, etc. and a thiourea. A base may for example be an inorganicbase (alkaline metal hydroxide such as sodium hydroxide and potassiumhydroxide, etc., alkaline metal hydrogen carbonate such as sodiumhydrogen carbonate and potassium hydrogen carbonate, etc., alkalinemetal carbonate such as sodium carbonate and potassium carbonate, etc.,a cesium salt such as cesium carbonate, etc., alkaline metal hydridesuch as sodium hydride and potassium hydride, etc., sodium amide,alkoxide such as sodium methoxide and sodium ethoxide, etc.) and anorganic base (amine such as trimethylamine, triethylamine anddiisopropylethylamine, cyclic amine such as pyridine, etc.).

[0346] In this reaction, 1 to 5 moles, preferably 1 to 3 moles of ansulfur-containing nucleophilic agent is employed per 1 mole of compound[XI] or a salt thereof. A base is employed also in an amount of 1 to 5moles, preferably 1 to 3 moles.

[0347] A reaction solvent is an alcohol such as methanol and ethanol,etc., an ether such as dioxane and tetrahydrofuran, etc., an aromatichydrocarbon such as benzene, toluene and xylene, etc., an ester such asethyl acetate, etc., a halogenated hydrocarbon such as chloroform anddichloromethane, etc., a nitrile such as acetonitrile, etc., an amidesuch as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and asulfoxide such as dimethylsulfoxide, etc.

[0348] While the reaction temperature may vary depending on the compoundemployed as well as other conditions, it is −20 to 200° C., preferably 0to 150° C. The reaction time is usually 5 minutes to 24 hours,preferably 5 minutes to 6 hours.

[0349] A sulfur-substituted product thus obtained is hydrolyzed with anacid or a base to yield compound [X]or a salt thereof.

[0350] An acid which may be employed is an inorganic acid such ashydrochloric acid, sulfuric acid and nitric acid, etc., and a base is aninorganic base (alkaline metal hydroxide such as sodium hydroxide andpotassium hydroxide, etc., alkaline metal hydrogen carbonate such assodium hydrogen carbonate and potassium hydrogen carbonate, etc.,alkaline metal carbonate such as sodium carbonate and potassiumcarbonate, etc.).

[0351] This reaction is conducted in a 20 to 50 volumes of an aqueoussolution of an inorganic acid described above (usually at 10 to 30%) per1 g of a sulfur-substituted product, or in an aqueous solutioncontaining 3 to 10 moles of a base described above per 1 mole of asulfur-substituted product. In view of the solubility of a compound, thereaction may be performed in an aqueous solution described above whichis supplemented with an organic solvent. An organic solvent which may beemployed is an alcohol such as methanol and ethanol, etc., an organicacid such as acetic acid, etc., an ether such as dioxane andtetrahydrofuran, etc., a nitrile such as acetonitrile, etc., an amidesuch as N,N-dimethylformamide and N,N-dimethylacetamide, etc. and asulfoxide such as dimethylsulfoxide, etc.

[0352] While the reaction temperature may vary depending on thesulfur-substituted product employed as well as other conditions, it is 0to 200° C., preferably 20 to 150° C. The reaction time is 30 minutes to48 hours, preferably 1 to 24 hours.

[0353] Compound [XI] may be a commercially available halogenateddicarboxylic acid derivative, a product obtained from a correspondingaminodicarboxylic acid derivative by substituting an amino group with ahalogen according to a method known in a literature such asHeterocycles, 24(5), 1331 (1986) or Journal of Organic Chemistry, 58(5),1159 (1993), etc., or a product obtained from a corresponding hydroxyform by converting into an appropriate leaving group according to amethod known in a literature such as an acylation or alkylationdescribed for example in Organic Functional Group Preparations (AcademicPress).

[0354] (Method E) A Compound Represented by Formula:

[0355] wherein q_(2d) is 0 to 2 and each of other symbols has a meaningdefined above which is encompassed within compound (I) of the inventionor a salt thereof can be produced for example by reacting a compoundrepresented by Formula:

[0356] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by R¹SH wherein R¹ has a meaning definedabove or a salt thereof in the presence of a base.

[0357] In this reaction, 1 to 5 moles, preferably 1 to 3 moles of acompound represented by R¹SH wherein R¹ has a meaning defined above or asalt thereof and 1 to 5 moles, preferably 1 to 3 moles of a base areemployed per 1 mole of Compound [XII] or a salt thereof. A compoundrepresented by R¹SH wherein R¹ has a meaning defined above which isemployed may for example be an inorganic sulfide such as hydrogensulfide, sodium hydrogen sulfide and sodium sulfide, etc., an aliphaticmercaptan such as methylmercaptan, ethylmercaptan and mercaptopropionicacid derivatives, etc., an organic sulfur-containing acid such asthioacetic acid and thiobenzoic acid, etc., an aromatic mercaptan suchas thiophenol, etc. and a thiourea, etc.

[0358] A base may for example be an alkaline metal hydroxide such assodium hydroxide and potassium hydroxide, etc., an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., an alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc., a cesium salt such as cesiumcarbonate, etc., an alkaline metal hydride such as sodium hydride andpotassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., an amine such as trimethylamine,triethylamine and diisopropylethylamine, etc., a cyclic amine such aspyridine, etc.

[0359] A reaction solvent which may be employed is an alcohol such asmethanol and ethanol, etc., an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc. Instead of using a base in this reaction, a compound represented byR¹SH may be converted for example into an alkaline metal salt or analkaline earth metal salt, which may then be reacted with compound [XII]or a salt thereof.

[0360] While the reaction temperature may vary depending on compound[XII] or a salt thereof employed as well as other reaction conditions,it is −20 to 200° C.” preferably 0 to 150° C. The reaction time is 5minutes to 24 hours, preferably 5 minutes to 6 hours.

[0361] A compound represented by Formula [XII] or a salt thereof may beproduced also for example by reacting a compound represented by Formula:

[0362] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0363] wherein each symbol has a meaning defined above or a salt thereofto form an amide followed by a hydrolysis and an imidation.

[0364] In this reaction, compound [XIII] or a salt thereof is firstcondensed with compound [II] or a salt thereof to form an amide.

[0365] This process may be in accordance with a known amidation such asa method described in “JIKKENKAGAKUKOZA”, Vol.22, Organic Synthesis IV(MARUZEN). A condensing agent may for example bedicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DEPC) anddiphenylphosphorylazide (DPPA),

[0366] When using such a condensing agent, an ordinary solvent (forexample, ethers, esters, hydrocarbons, amides and sulfoxides, etc.including tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate,benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide, etc.) isemployed.

[0367] This reaction may be promoted in the presence of a base at atemperature of −10 to 100° C., preferably 0 to 60° C.

[0368] The reaction time is usually 30 minutes to 96 hours, preferably 1to 72 hours. The amount of compound [II] or a salt thereof and acondensing agent employed is 1 to 5 moles, preferably 1 to 3 moles per 1mole of compound [XIII] or a salt thereof.

[0369] A base may for example be an alkylamine such as triethylamine,etc. and a cyclic amine such as N-methylmorpholine and pyridine, etc.,and is used in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1mole of compound [XIII] or a salt thereof.

[0370] An ester thus obtained can be hydrolyzed to obtain a carboxylicacid. A hydrolysis may be effected using an acid or a base.

[0371] An acid which may be employed may for example be an inorganicacid such as hydrochloric acid, sulfuric acid and nitric acid, and abase may for example be an inorganic base (alkaline metal hydroxide suchas sodium hydroxide and potassium hydroxide, etc., alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc.).

[0372] This reaction is conducted in a 20 to 50 volumes of an aqueoussolution of an inorganic acid described above (usually at 10 to 30%) per1 g of an ester, or in an aqueous solution containing 3 to 10 moles of abase described above per 1 mole of an ester. In view of the solubilityof a compound, the reaction may be performed in an aqueous solutiondescribed above which is supplemented with an organic solvent. Anorganic solvent which may be employed is an alcohol such as methanol andethanol, etc., an organic acid such as acetic acid, etc., an ether suchas dioxane and tetrahydrofuran, etc., a nitrile such as acetonitrile,etc., an amide such as N,N-dimethylformamide, etc. andN,N-dimethylacetamide and a sulfoxide such as dimethylsulfoxide, etc.

[0373] While the reaction temperature may vary depending on the esteremployed as well as other conditions, it is 0 to 200° C., preferably 20to 150° C. The reaction time is 30 minutes to 48 hours, preferably 1 to24 hours.

[0374] A carboxylic acid thus obtained can be condensed to yieldcompound [XII] or a salt thereof.

[0375] This reaction employs 10 to 50 volumes of a condensing agent as areaction solvent per 1 g of a carboxylic acid. A condensing agent is ananhydride of an ordinary organic acid such as acetic anhydride andbenzoic anhydride, etc. The addition of a base in this reaction allowsthe reaction to proceed advantageously.

[0376] A base which may be employed is preferably an alkaline metal saltof an organic acid corresponding to a condensing agent employed such assodium acetate and potassium acetate. The amount is 0.1 to 1 mole basedon a carboxylic acid.

[0377] While the reaction temperature may vary depending on thecarboxylic acid employed as well as other conditions, it is 20 to 200°C., preferably 50 to 150° C. The reaction time is 5 minutes to 24 hours,preferably 5 minutes to 5 hours.

[0378] As compound [VIII], a commercially available epoxysuccinic acidderivative is mainly employed.

[0379] (Method F) A Compound Represented by Formula:

[0380] wherein q_(2e) is 2n+1 and each of other symbols has a meaningdefined above which is encompassed within compound (I) of the inventionor a salt thereof can be produced for example by subjecting a compoundrepresented by Formula:

[0381] wherein each symbol has a meaning defined above or a salt thereofto a method similar to that in method C described above in the presenceof a base.

[0382] A compound represented by Formula (XIV) or a salt thereof can beproduced also by reacting a compound represented by Formula:

[0383] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0384] wherein each symbol has a meaning defined above or a salt thereofto form an amide followed by reacting with a compound represented byR¹SH wherein R¹ has a meaning defined above or a salt thereof followedby an amidation.

[0385] In this amidation, 1 mole of compound [XV] or a salt thereof isreacted with 1 to 5 moles, preferably 1 to 2 moles of compound [II] or asalt thereof.

[0386] A reaction solvent may for example be an alcohol such as methanoland ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc.,an aromatic hydrocarbon such as benzene, toluene and xylene, etc., anester such as ethyl acetate, etc., a halogenated hydrocarbon such aschloroform and dichloromethane, etc., a nitrile such as acetonitrile,etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide,etc. and a sulfoxide such as dimethylsulfoxide, etc.

[0387] While the reaction temperature may vary depending on compound[XV] or a salt thereof as well as other conditions, it is −20 to 100°C., preferably 0 to 100° C. The reaction time is 5 minutes to 5 hours,preferably 5 minutes to 1 hour.

[0388] An amide thus obtained can be converted into an adduct by amethod similar to that in (Method B) described above, and then condensedby a method similar to that in (Method E), whereby producing compound[XIV] or a salt thereof.

[0389] As compound [XV], a commercially available itaconic anhydridederivative is mainly employed.

[0390] (Method G) Compound (I) according to the invention or a saltthereof can be produced for example by reacting a compound representedby Formula:

[0391] wherein L² is a leaving group and each of other symbols has ameaning defined above or a salt thereof with a compound represented byR¹SH wherein R¹ has a meaning defined above or a salt thereof in thepresence of a base.

[0392] A leaving group represented by L² described above may forexample-be one exemplified as a leaving group-as represented by L¹described above.

[0393] A compound represented by Formula (XVI) or a salt thereof can beproduced for example from a compound represented by Formula:

[0394] wherein each symbol has a meaning defined above or a saltthereof.

[0395] Thus, compound [XVI] or a salt thereof can be produced bydecarboxylating compound [XVII] or a salt thereof and then reacting adicarbonyl compound thus formed in situ with a nucleophilic agent or areducing agent to form a hydroxy product which is then converted into aleaving group.

[0396] A decarboxylation is performed in 1 to 100 volumes, preferably 20to 50 volumes of a solvent per 1 g of compound [XVII]. While a solventwhich may preferably be employed is a nitrile such as acetonitrile,etc., those also employed are an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., an amide suchas N,N-dimethylformamide and N,N-dimethylacetamide, etc., a sulfoxidesuch as dimethylsulfoxide, etc. as well as water.

[0397] While the reaction temperature may vary depending on compound[XVII] or a salt thereof employed as well as other conditions, it is 0to 200° C., preferably 20 to 150° C. The reaction time is 5 minutes to24 hours, preferably 5 minutes to 1 hour.

[0398] In a nucleophilic reaction and a reducing reaction, anucleophilic agent or a reducing agent is employed in an amount of 1 to5 moles, preferably 1 to 3 moles per 1 mole of compound [XVII] or a saltthereof. A nucleophilic agent may be an organic metal reagent such asorganic lithium, organic zinc, organic aluminum, Grignard reagent, etc.While a reducing agent may preferably be a metal hydride such as sodiumborohydride as lithium aluminum hydride, etc., it may be a reagentcapable of reducing a ketone compound to an alcohol, such as onedescribed in “SHINJIKKENKAGAKUKOZA”, Vol.15, Oxidation and Reduction(MARUZEN).

[0399] A solvent which may be employed may for example be an alcoholsuch as methanol and ethanol, etc., an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc.

[0400] While the reaction temperature may vary depending on the reagentemployed as well as other conditions, it is −100 to 200° C., preferably−78 to 100° C. The reaction time is 5 minutes to 24 hours, preferably 5minutes to 10 hours.

[0401] A resultant hydroxy product can be converted into any of variousleaving groups to produce compound [XVI]. Such leaving group may forexample be a halogen atom (for example, chlorine, bromine and iodine,etc.), a substituted sulfonyloxy (for example, methanesulfonyloxy andp-toluenesulfonyloxy, etc.), an acyloxy (for example, acetoxy andbenzoyloxy, etc.) and an oxy group which is substituted with aheterocyclic or aryl group (such as succinimide, benzotriazole,quinoline and 4-nitrophenyl, etc.), etc.

[0402] A halogen atom may for example be a halide of an inorganic acid,such as thionyl chloride, thionyl bromide, phosphorus trichloride,phosphorus pentachloride and phosphorus oxychloride, etc. and ahalogenated hydrogen acid such as hydrochloric acid and hydrobromicacid, etc. Other leaving groups can be produced by known methods such asthose described in method D for producing compound [XI].

[0403] For example, a latter reaction employing an acylation employs 1to 5 moles, preferably 1 to 2 moles of a corresponding halide and 1 to 5moles, preferably 1 to 3 moles of a base per 1 mole of a hydroxy productor a salt thereof. Some base, such as pyridine, can serve also as asolvent.

[0404] A solvent may for example be an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc.; a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc.

[0405] A base may for example be an alkaline metal hydroxide such assodium hydroxide and potassium hydroxide, etc., an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., an alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc., a cesium salt such as cesiumcarbonate, etc., an alkaline metal hydride such as sodium hydride andpotassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., an amine such as trimethylamine,triethylamine and diisopropylethylamine, etc., a cyclic amine such aspyridine, etc.

[0406] While the reaction temperature may vary depending on thesubstrate employed as well as other conditions, it is −20 to 200° C.,preferably 0 to 100° C. The reaction time is 30 minutes to 48 hours,preferably 1 to 24 hours.

[0407] A resultant compound can be subjected to a method similar to thatin (Method D) described above to react with any of varioussulfur-containing nucleophilic agents to produce compound [I] wherein R¹is not H or a salt thereof and also to be deprotected to producecompound [I] wherein R¹ is H or a salt thereof.

[0408] Alternatively, a compound represented by Formula (XVII) or a saltthereof can be produced for example by reacting a compound representedby Formula:

[0409] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0410] wherein each symbol has a meaning defined above or a saltthereof, or with a compound represented by Formula:

[0411] wherein X₁ is a halogen atom and each of other symbols has ameaning defined above or a salt thereof to form an amide, which is thensubjected to a treatment with a base.

[0412] A halogen atom represented by X¹ may for example be fluorine,chlorine, bromine and iodine, etc.

[0413] In this reaction, compound [XVIII] or a salt thereof can becondensed with compound [XIX] or a salt thereof using a condensing agentor its halide [XX] or a salt thereof can be reacted in the presence of abase to form an amide. The former reaction can be performed similarly to(Method E) described above.

[0414] The latter reaction employs 1 to 5 moles, preferably 1 to 2 molesof compound [XX] or a salt thereof per 1 mole of compound [XVIII] or asalt thereof. A base may for example be an alkaline metal hydroxide suchas sodium hydroxide and potassium hydroxide, etc., an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., an alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc., a cesium salt such as cesiumcarbonate, etc., an alkaline metal hydride such as sodium hydride andpotassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., an amine such as trimethylamine,triethylamine and diisopropylethylamine, etc., a cyclic amine such aspyridine, etc. The amount of a base employed is 1 to 10 moles,preferably 1 to 5 moles per 1 moles of compound [XVIII] or a saltthereof. Some base, such as pyridine, can serve also as a solvent.

[0415] A solvent may for example be an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc. While the reaction temperature may vary depending on compound[XVIII] or a salt thereof employed as well as other conditions, it is−20 to 200° C., preferably 0 to 100° C. The reaction time is 5 minutesto 48 hours, preferably 5 minutes to 24 hours.

[0416] A resultant amide can be subjected to a treatment with a base toproduce compound [XVII] or a salt thereof.

[0417] This reaction employs 1 to 3 moles, preferably 1 to 2 moles of abase per 1 mole of an amide. A base may for example be an alkaline metalhydroxide such as sodium hydroxide and potassium hydroxide, etc., analkaline metal hydrogen carbonate such as sodium hydrogen carbonate andpotassium hydrogen carbonate, etc., an alkaline metal carbonate such assodium carbonate and potassium carbonate, etc., a cesium salt such ascesium carbonate, etc., an alkaline metal hydride such as sodium hydrideand potassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc. A solvent which may be employed mayfor example be an alcohol such as methanol and ethanol, etc., an ethersuch as dioxane and tetrahydrofuran, etc., an aromatic hydrocarbon suchas benzene, toluene and xylene, etc., an ester such as ethyl acetate,etc., a halogenated hydrocarbon such as chloroform and dichloromethane,etc., a nitrile such as acetonitrile, etc., an amide such asN,N-dimethylformamide and N,N-dimethylacetamide, etc. and a sulfoxidesuch as dimethylsulfoxide, etc. While the reaction temperature may varydepending on the amide employed as well as other conditions, it is −20to 200° C., preferably 0 to 100° C. The reaction time is 5 minutes to 48hours, preferably 10 minutes to 5 hours.

[0418] Alternatively, a compound represented by Formula (XVIII) or asalt thereof can be produced for example by reacting a compoundrepresented by Formula:

[0419] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0420] wherein each symbol has a meaning defined above or a saltthereof.

[0421] Compound [XVIII] or a salt thereof can be produced from compound[XXI] or a salt thereof and a carbonyl compound [XXII] by an in situproduction of an imine which is then reduced by an appropriate reducingagent.

[0422] A reducing agent Is preferably sodium borohydride, lithiumborohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

[0423] In this reaction, 1 to 5 moles, preferably 1 to 2 moles ofcarbonyl compound [XXII] and 0.5 to 10 moles, preferably 0.5 to 3 molesof a reducing agent per 1 mole of compound [XXI] or a salt thereof. Areaction solvent may for example be an alcohol such as methanol andethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., anaromatic hydrocarbon such as benzene, toluene and xylene, etc., an estersuch as ethyl acetate, etc., a halogenated hydrocarbon such aschloroform and dichloromethane, etc., a nitrile such as acetonitrile,etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide,etc. and a sulfoxide such as dimethylsulfoxide, etc.

[0424] When producing an imine, a dehydrating condition using amolecular sieve or an addition of an acid serves to promote thereaction. An acid employed here is preferably acetic acid andtrifluoroacetic acid, etc. While the reaction temperature in this imineproduction may vary depending on compound [XXI] or a salt thereof aswell as other conditions, it is 0 to 200° C., preferably 0 to 150° C.The reaction time is 30 minutes to 48 hours, preferably 1 hour to 24hours.

[0425] The reaction temperature in the reducing reaction is −20 to 150°C., preferably 0 to 100° C. The reaction time is 30 minutes to 24 hours,preferably 30 minutes to 12 hours.

[0426] Compound [XXI] is mainly a commercially available amino acidderivative, while compound [XXII] is produced by method N or acommercially available product. (Method H) A compound represented byFormula:

[0427] wherein R¹ is an optionally substituted hydrocarbon group, anacyl group or an optionally substituted heterocyclic group, and each ofother symbols has a meaning defined above which is encompassed withincompound (I) of the invention or a salt thereof can be produced forexample by reacting a compound represented by Formula:

R¹SH  [XXIII]

[0428] wherein R¹ has a meaning defined above or a salt thereof with acompound represented by Formula (IX) described above or a salt thereofby a method similar to (Method C) described above or by a method knownper se.

[0429] Alternatively, a compound represented by Formula (XXIII) or asalt thereof is commercially available or can be produced from acompound represented by Formula:

R¹X₁  [XXIV]

[0430] wherein each symbol has a meaning defined above or a salt thereofin accordance with a method known in a literature (for example, methodsexemplified in Organic Chemistry of Bivalent Sulfur, Vol.1, p32 (Chem.Publ. Co., New York), Organic Functional Group Preparations, 1(Academic), etc.).

[0431] An ‘optionally substituted’ hydrocarbon group represented byFormula R¹ may for example be one exemplified as an “optionallysubstituted hydrocarbon group” represented by R¹ described above. An“acyl group” represented by Formula R¹ may for example be oneexemplified as an “acyl group” represented by R¹ described above.

[0432] An “optionally substituted heterocyclic group” represented byFormula R¹ may for example be one exemplified as an “optionallysubstituted heterocyclic group” represented by R¹ described above.

[0433] (Method I) A Compound Represented by Formula:

[0434] wherein q_(2f) is 0 to 2n+2 and each of other symbols has ameaning defined above which is encompassed within compound (I) of theinvention or a salt thereof can be produced for example by subjecting acompound represented by Formula:

[0435] wherein L³ is a leaving group and each of other symbols has ameaning defined above or a salt thereof and a compound represented byR¹SH wherein R¹ has a meaning defined above or a salt thereof to anucleophilic reaction.

[0436] A leaving group represented by L³ may for example be oneexemplified as a leaving group represented by L¹ described above.

[0437] This reaction can be performed in accordance with a methodsimilar to (Method G) described above.

[0438] Alternatively, a compound represented by Formula: (XXV) or a saltthereof can be produced for example by converting a secondary hydroxygroup of a compound represented by Formula:

[0439] wherein each symbol has a meaning defined above or a salt thereofto a leaving group.

[0440] In this reaction, a primary hydroxy group of compound [XXVI] or asalt thereof is first protected to form a protected intermediate.

[0441] While a protective group employed in this reaction may be any ofthe protective groups for a hydroxy group employed generally, it ispreferably a triphenylmethyl group, a diphenylmethyl group, atbutyldimethylsilyl group or a t-butyldiphenylsilyl group, etc. having alarge steric hindrance, since a secondary hydroxy group existssimultaneously. In the reaction, a halide having a substituent listedabove, such as a triphenylmethyl chloride, etc., is condensed withcompound [XXVI] or a salt thereof in the presence of a base to form aprotected intermediate.

[0442] In this reaction, 1 to 5 moles, preferable 1 to 3 moles of ahalide and 1 to 10 moles, preferably 1 to 5 moles of a base are employedper 1 mole of compound [XXVI] or a salt thereof.

[0443] A base may for example be an alkaline metal hydroxide such assodium hydroxide and potassium hydroxide, etc., an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., an alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc., a cesium salt such as cesiumcarbonate, etc., an alkaline metal hydride such as sodium hydride andpotassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., an amine such as trimethylamine,triethylamine and diisopropylethylamine, etc., a cyclic amine such aspyridine, etc.

[0444] A solvent may for example be an ether such as dioxane andtetrahydrofuran, etc., an aromatic hydrocarbon such as benzene, tolueneand xylene, etc., an ester such as ethyl acetate, etc., a halogenatedhydrocarbon such as chloroform and dichloromethane, etc., a nitrile suchas acetonitrile, etc., an amide such as N,N-dimethylformamide andN,N-dimethylacetamide, etc. and a sulfoxide such as dimethylsulfoxide,etc.

[0445] While the reaction temperature may vary depending on thesubstrate employed as well as other conditions, it is −20 to 200° C.,preferably 0 to 100° C. The reaction time is 1 to 48 hours, preferably 1to 24 hours.

[0446] An intermediate thus obtained can be subjected to a methodsimilar to that in (Method G) described above to convert a secondaryhydroxy group into a leaving group.

[0447] An active intermediate thus obtained is deprotected to yieldcompound [XXV] or a salt thereof.

[0448] In this reaction, a deprotection is effected under an acidiccondition or as a catalytic hydrogenation. A catalyst employed in acatalytic hydrogenation may for example be a platinum catalyst such asplatinum black, platinum oxide and Pt/C, etc., a palladium catalyst suchas palladium black, palladium oxide, palladium barium sulfate, Pd/C,etc. and nickel catalyst such as reduced nickel, oxidized nickel, Raneynickel, Urushibara nickel catalyst, etc.

[0449] A solvent is preferably an alcohol such as methanol, ethanol,propanol and isopropanol, etc., an ether such as tetrahydrofuran anddioxane, etc. and an ester such as ethyl acetate, etc.

[0450] The reaction temperature is 0° C. to 200° C., preferably 20° C.to 110° C. The reaction time is usually 0.5 to 48 hours, preferably 1 to16 hours. While a reaction is performed usually in an atmosphericpressure, it can be performed under pressure (3 to 10 atm) if necessary.

[0451] While the amount of a catalyst employed may vary depending on thetype of the catalyst employed, it is usually 0.1 to 20% by weight basedon an active intermediate or a salt thereof.

[0452] An acid employed in a deprotection under an acidic condition mayfor example be an inorganic acid such as hydrochloric acid, sulfuricacid and nitric acid, etc., and an ordinary organic acid such as formicacid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc.as well as a Lewis acid.

[0453] A reaction solvent may for example be an alcohol such as methanoland ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc.,an aromatic hydrocarbon such as benzene, toluene and xylene, etc., anester such as ethyl acetate, etc., a halogenated hydrocarbon such aschloroform and dichloromethane, etc., a nitrile such as acetonitrile,etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide,etc. and a sulfoxide such as dimethylsulfoxide, etc.

[0454] This reaction employs 1 to 100 moles, preferably 1 to 10 moles ofan acid described above per 1 mole of an active intermediate. Some acidcan serve also as a solvent.

[0455] While the reaction temperature may vary depending on thesubstrate employed as well as other conditions, it is −20 to 200° C.,preferably 0 to 100° C. The reaction time is usually 5 minutes to 24hours, preferably 5 minutes to 10 hours.

[0456] A compound represented by Formula (XXVI) or a salt thereof can beproduced for example by subjecting a compound represented by Formula:

[0457] wherein each symbol has a meaning defined above or a salt thereofto a reaction similar to that in Method G or to a method known per se.

[0458] A compound represented by Formula (XXVII) or a salt thereof canbe produced for example by subjecting a compound represented by Formula:

[0459] wherein each symbol has a meaning defined above or a salt thereofto a deprotection.

[0460] While this reaction can be performed various methods, forexample, the reductive method similar to catalytic hydrogenation ispreferably employed.

[0461] A compound represented by Formula (XXVIII) or a salt thereof canbe produced for example by subjecting a compound represented by Formula:

[0462] wherein each symbol has a meaning defined above or a salt thereofto a reaction similar to that in Method G or to a method known per se.

[0463] As Compound [XXIX], a commercially available amino acidderivative such as serine, etc. is employed mainly.

[0464] (Method J) A Compound Represented by Formula:

[0465] wherein each symbol has a meaning defined above which isencompassed within compound (I) of the invention or a salt thereof canbe produced for example by reacting a compound represented by Formula:

[0466] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0467] wherein each symbol has a meaning defined above or a saltthereof.

[0468] This reaction can be performed by a method in (Method A)described above or an analogous method.

[0469] As compound [XXX], a commercially available thiodisuccinic acidmay for example be employed.

[0470] (Method K) A Compound Represented by Formula:

[0471] wherein each symbol has a meaning defined above which isencompassed within compound (I) of the invention or a salt thereof canbe produced for example by reacting a compound represented by Formula:

[0472] wherein L⁴ is a leaving group and each of other symbols has ameaning defined above or a salt thereof with a compound represented byR¹SH wherein R¹ has a meaning defined above or a salt thereof.

[0473] A leaving group represented by L⁴ may for example be oneexemplified as a leaving group represented by L¹ described above.

[0474] This reaction can be performed by a method similar to that in(Method G) described above.

[0475] Alternatively, a compound represented by Formula (XXXI) or a saltthereof can also be produced for example by reacting a compoundrepresented by Formula:

[0476] or a salt thereof with a compound represented by Formula:

[0477] wherein each symbol has a meaning defined above or a salt thereofto form an imide followed by a deprotection to form an amino product anda conversion of an amino group to a halogen.

[0478] In this reaction, compound [XXXII] or a salt thereof is firstcondensed with compound [II] or a salt thereof by a method similar tothat in (Method E) described above to produce imide. In this process, acyclization occurs simultaneously.

[0479] A deprotection of an imide thus obtained yields an amino productor a salt thereof. This reaction is performed using 1 g of an imideproduct in 10 volumes of an appropriate organic acid solvent or aninorganic aqueous solution or a mixture. An organic acid is preferablytrifluoroacetic acid, etc. An inorganic acid is preferably hydrochloricacid, sulfuric acid, etc.

[0480] The reaction temperature is −20 to 100° C., preferably −20 to 50°C. The reaction time is usually 1 minute to 24 hours, preferably 1minute to 12 hours.

[0481] A resultant amino product or a salt thereof can be substituted bya halogen by a method known in literature, such as methods described inHeterocycles, 24(5), 1331 (1986) and Journal of Organic Chemistry,58(5), 1159 (1993) to produce compound [XXXI]

[0482] In this reaction, 1 to 10 moles, preferably 1 to 3 moles of adiazotizing agent such as sodium nitrite, etc. is reacted per 1 mole ofan amino product or a salt thereof in the presence of 1 to 100 moles ofa haloacid. A haloacid is preferably hydrochloric acid, hydrobromic acidand hydroiodic acid, etc.

[0483] As a reaction solvent, a nitrile such as acetonitrile, etc. andwater are preferred.

[0484] The reaction temperature is −50 to 100° C., preferably −20 to 50°C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to12 hours. Alternatively, a compound represented by Formula (XXXII) or asalt thereof can be produced for example by a compound represented byFormula:

[0485] by a method known in a literature (Tetrahedron Asymmetry, 6(6),1249 (1995)).

[0486] (Method L) A Compound Represented by Formula:

[0487] wherein each symbol has a meaning defined above which isencompassed within compound (I) of the invention or a salt thereof canbe produced for example by reacting a compound represented by Formula:

[0488] wherein L⁵ is a leaving group and each of other symbols has ameaning defined above or a salt thereof with a compound represented byR¹SH wherein R¹ has a meaning defined above or a salt thereof.

[0489] This reaction can be performed by a method described in (MethodG) or an analogous method.

[0490] A leaving group represented by L⁵ may for example be oneexemplified as a leaving group represented by L¹ described above.

[0491] Alternatively, a compound represented by Formula (XXXV) or a saltcan also be produced for example by reacting a compound represented byFormula:

[0492] wherein each symbol has a meaning defined above or a salt thereofwith a compound represented by Formula:

[0493] wherein L⁶ is a leaving group and each of other symbols has ameaning defined above or a salt thereof to convert a hydroxy group intoa leaving group.

[0494] A leaving group represented by L⁶ may for example be a halogenatom (for example, chlorine, bromine and iodine, etc.), a substitutedsulfonyloxy (for example, methanesulfonyloxy and p-toluenesulfonyloxy,etc.), an acyloxy (such as acetoxy and benzoyloxy, etc.), and an oxygroup substituted by a heterocyclic ring or an aryl group (such assuccinimide, benzotriazole, quinoline and 4-nitrophenyl, etc.).

[0495] Compound [XXXVI] or a salt thereof may be used as a free form, itmay be subjected to a reaction as an alkaline metal salt such aslithium, sodium and potassium salts, etc.

[0496] In this reaction, 1 to 10 moles, preferably 1 to 5 moles ofcompound [IIa] or a salt thereof is reacted per 1 mole of compound[XXXVI] or a salt thereof.

[0497] Usually, the reaction is performed in a solvent. Such solvent mayfor example be a halogenated hydrocarbon such as dichloromethane andchloroform, etc., a nitrile such as acetonitrile, etc., an ether such asdimethoxyethane and tetrahydrofuran, etc. as well as dimethylformamide,dimethylsulfoxide and hexamethylphosphoramide, etc.

[0498] The addition of a base in this reaction allows the reaction toproceed advantageously. Such base may for example be sodium hydrogencarbonate, potassium hydrogen carbonate, sodium carbonate, potassiumcarbonate, sodium hydride, potassiumhydride, sodium amide,sodiummethoxide, triethylamine, diisopropylethylamine and pyridine, etc.

[0499] While the amount of a base may vary depending on the types of thecompound and the solvent employed as well as other reaction conditions,it is usually 1 to 10 moles, preferably 1 to 5 moles per 1 mole ofcompound [XXXVI] or a salt thereof. The reaction temperature is about−50 to 200° C., preferably −20 to 150° C. While the reaction time—variesdepending on the type of the compound and the reaction temperature, itis 1 to 72 hours, preferably 1 to 24 hours.

[0500] Compound [XXXVI] may be any of commercially availablehydroxy-substituted 5-membered and 6-membered amides such as(S)-4-hydroxypyrrolidin-2-one, (R)-4-hydroxypyrrolidin-2-one (DAISO),3-hydroxypiperidin-2-one (Aldrich), etc., or may be produced by a methodknown in literatures such as Synthesis, 614 (1978), TetrahedronAsymmetry, 3(11), 1431 (1992), etc.

[0501] Compound [IIa] may be a commercially available product or may beproduced by Method N.

[0502] (Method M) A compound represented by Formula:

[0503] wherein each symbol has a meaning defined above which isencompassed within compound (I) of the invention or a salt thereof canbe produced for example from a compound represented by Formula:

[0504] wherein L⁷ is a leaving group and each of other symbols has ameaning defined above or a salt thereof by a method similar to Method Gdescribed above.

[0505] A leaving group represented by L⁷ may for example be oneexemplified as a leaving group represented by L¹ described above.

[0506] Alternatively, a compound represented by Formula [XXXVIII] or asalt thereof can also be produced for example by subjecting a compoundrepresented by Formula:

[0507] wherein Bz is a benzyl group and each of other symbols has ameaning defined above or a salt thereof to a catalytic hydrogenation bya method known per se (for example a method similar to Method Idescribed above) to obtain a saturated hydroxy form which is thenconverted into a leaving group.

[0508] Compound [XXXIX] or a salt thereof can be produced also inaccordance with a method known in a literature (Journal of AmericanChemical Society, 75, 3413 (1953)). For example, a compound representedby Formula:

[0509] wherein R^(b) is an optionally substituted hydrocarbon group andY has a meaning defined above or a salt thereof is subjected to a methodsimilar to Method G described above to form a reduced amino productwhich is then reacted with a diester derivative of oxalic acid in thepresence of a base.

[0510] An optionally substituted hydrocarbon group represented by R^(b)may for example be one exemplified as an optionally substitutedhydrocarbon group represented by R¹ described above, with a benzyl groupbeing preferred.

[0511] In this reaction, a diester of oxalic acid and a base areemployed in amounts of 1 to 3 moles, preferably 1 to 2 moles per 1 moleof a reduced amino product.

[0512] While various diester derivatives of oxalic acid may be employed,a benzyl derivative capable of being deprotected by a catalytichydrogenation is preferred.

[0513] A base may for example be an alkaline metal hydroxide such assodium hydroxide and potassium hydroxide, etc., an alkaline metalhydrogen carbonate such as sodium hydrogen carbonate and potassiumhydrogen carbonate, etc., an alkaline metal carbonate such as sodiumcarbonate and potassium carbonate, etc., a cesium salt such as cesiumcarbonate, etc., an alkaline metal hydride such as sodium hydride andpotassium hydride, etc., sodium amide, an alkoxide such as sodiummethoxide and sodium ethoxide, etc., an amine such as trimethylamine,triethylamine and diisopropylethylamine, etc., a cyclic amine such aspyridine, etc.

[0514] A reaction solvent may for example be an alcohol such as methanoland ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc.,an aromatic hydrocarbon such as benzene, toluene and xylene, etc., anester such as ethyl acetate, etc., a halogenated hydrocarbon such aschloroform and dichloromethane, etc., a nitrile such as acetonitrile,etc., an amide such as N,N-dimethylformamide and N,N-dimethylacetamide,etc. and a sulfoxide such as dimethylsulfoxide, etc. as well as water,etc.

[0515] While the reaction temperature may vary depending on thesubstrate employed as well as other conditions, it is 0 to 200° C.,preferably 0 to 150° C. The reaction time is 1 to 24 hours, preferably 1to 12 hours.

[0516] (Method N) A compound represented by Formula:

[0517] or a salt thereof, wherein R²⁶ has a meaning-similar to that of asubstituent on ring B in Formula [I] shown above and R³⁰ is an aminogroup or a halogen which is encompassed within a compound [II] or [IIa]described above or a salt thereof can be produced for example bysubjecting a compound represented by Formula:

[0518] wherein R²⁶ has a meaning defined above and W is a cyano group oran aldehyde group or a salt thereof to a reduction or a halogenationwhich is known per se.

[0519] Compound [XXXXII] wherein W is a nitrile was reduced by a knownmethod, such as one using an appropriate reducing agent described forexample in “SHINJIKKENKAGAKUKOZA”, Vol.15, Oxidation and Reduction(MARUZEN) to form a benzylamine product [XXXXI]. As a reducing agent, anordinary nitrile reducing reagent such as a metal hydride includinglithium aluminum hydride, etc.

[0520] In this reaction 0.5 to 3 moles, preferably 0.5 to 1 mole of areducing agent is employed per 1 mole of Compound [XXXXII].

[0521] As a reaction solvent, an ether such as dioxane andtetrahydrofuran, etc. and an aromatic hydrocarbon such as benzene,toluene and xylene, etc. may be employed.

[0522] The reaction temperature is −50 to 100° C., preferably 0 to 80°C. The reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.

[0523] A compound [XXXXII] wherein W was an aldehyde was subjected to aknown method such as those described in “JIKKENKAGAKUKOZA”, Vol.20,(MARUZEN) and Journal of American Chemical Society, 81, 475 (1959) byconverting into an oxime using hydroxylamine followed by a reductionwith an appropriate reducing agent to yield a benzylamine product[XXXXI].

[0524] An oxime production uses 1 to 3 moles, preferably 1 to 2 moles ofhydroxylamine per 1 mole of an aldehyde. This reaction is promoted by anaddition of a base. Such base may for example be an alkaline metalhydroxide such as sodium hydroxide and potassium hydroxide, etc., analkaline metal hydrogen carbonate such as sodium hydrogen carbonate andpotassium hydrogen carbonate, etc., an alkaline metal carbonate such assodium carbonate and potassium carbonate, etc., sodium amide, analkoxide such as sodium methoxide and sodium ethoxide, etc., an aminesuch as trimethylamine, triethylamine and diisopropylethylamine, etc., acyclic amine such as pyridine, etc. The amount employed is 1 to 5 moles,preferably 1 to 3 moles per 1 mole of an aldehyde.

[0525] A reaction solvent may for example be an alcohol such as methanoland ethanol, etc., an ether such as dioxane and tetrahydrofuran, etc., anitrile such as acetonitrile, etc., an amide such asN,N-dimethylformamide and N,N-dimethylacetamide, etc., a sulfoxide suchas dimethylsulfoxide, etc. as well as water, etc. The reactiontemperature is 0 to 200° C., preferably 0 to 150° C., and the reactiontime is 1 to 48 hours, preferably 1 to 24 hours.

[0526] In addition to a catalytic hydrogenation, any ordinary oximereducing agent such as a metal hydride including lithium aluminumhydride, etc. can be employed as a reducing agent as described in“SHINJIKKENKAGAKUKOZA”, Vol. 15, Oxidation and Reduction (MARUZEN). Thereaction condition is similar to that for reducing a nitrile.

[0527] When W is an aldehyde, an appropriate reducing agent was used toform a hydroxy product and then the hydroxy group was halogenated usinga halogenating agent to obtain a benzyl halide [XXXXI]. A reducing agentmay be an ordinary aldehyde reducing agent described in“SHINJIKKENKAGAKUKOZA”, Vol. 15, Oxidation and Reduction with sodiumborohydride and lithium aluminum hydride, etc. being employedpreferably. The reaction condition is similar to that for a nitriledescribed above.

[0528] A halogenating agent may for example be a halide of an inorganicacid, such as thionyl chloride, thionyl bromide, phosphorus trichloride,phosphorus pentachloride and phosphorus oxychloride, etc. and ahalogenated hydrogen acid such as hydrochloric acid and hydrobromicacid, etc.

[0529] In this reaction, 1 to 3 moles, preferably 1 to 1.5 moles of ahalogenating agent is employed per 1 mole of an alcohol.

[0530] This reaction is promoted by an addition of a base. Such base mayfor example be an amine such as trimethylamine, triethylamine anddiisopropylethylamine, etc. and a cyclic amine such as pyridine, etc.

[0531] A reaction solvent may for example be an ether such as dioxaneand tetrahydrofuran, etc., an aromatic hydrocarbon such as benzene,toluene and xylene, etc., an ester such as ethyl acetate, etc., and ahalogenated hydrocarbon such as chloroform and dichloromethane, etc.

[0532] The reaction temperature is −50 to 100° C., preferably −20 to 50°C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to10 hours.

[0533] Alternatively, compound [XXXXII] may be a commercially availableproduct or may be produced from a compound represented by Formula:

[0534] wherein W has a meaning defined above and X is a halogen atom ora salt thereof and a compound represented by Formula:

[0535] wherein R²⁶ has a meaning defined above or a salt thereof by amethod known per se ((Journal of Organic Chemistry, 59(18), 5414 (1994),Bioorganic and Medicinal Chemistry, 6, 15 (1998)) as well as ananalogous method.

[0536] Compound (I) obtained by any method described above as a freeform may be converted in accordance with a standard procedure forexample into a salt with an inorganic acid (for example, hydrochloricacid, sulfuric acid and hydrobromic acid, etc.), an organic acid (forexample, methanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, oxalic acid, fumaric acid, maleic acid and tartaric acid, etc.),an inorganic base (for example, alkaline metal such as sodium andpotassium, etc., alkaline earth metal such as calcium and magnesium,etc., aluminum and ammonium, etc.) or an organic base (for example,trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine andN,N′-dibenzylethylenediamine, etc.), while compound (I) obtained as asalt may be converted into a free form or other salts according to astandard procedure.

[0537] Compound (I) or a salt thereof thus obtained can be purified andrecovered using a separation/purification method known per se (forexample, condensation, solvent extraction, column chromatography andrecrystallization, etc.).

[0538] A starting compound for compound (I) according to the inventionmay be in a form of a salt, including a salt with an inorganic acid (forexample, hydrochloric acid, phosphoric acid, hydrobromic acid andsulfuric acid, etc.) and a salt with an organic acid (for example,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.). Whenany of these compound carries an acidic group such as —COOH, etc., asalt with an inorganic base (for example, an alkaline metal or analkaline earth metal such as sodium, potassium, calcium and magnesium,ammonia, etc.) or with an organic base (for example, tri-C₁₋₃ alkylaminesuch as triethylamine, etc.) may be formed.

[0539] In each of the reactions described above, when a startingcompound carries as a substituent an amino group, a carboxyl group or ahydroxyl group, then such group is derivatized with a protective groupemployed ordinarily in a peptide chemistry, which is cleaved after areaction if desired to yield an intended compound.

[0540] A protective group for an amino group may for example be anoptionally substituted C₁₋₆ alkylcarbonyl (for example, formyl,methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a C₁₋₆alkyloxycarbonyl (for example, methoxycarbonyl and ethoxycarbonyl,etc.), phenyloxycarbonyl (for example, benzoxycarbonyl), C₇₋₁₀aralkylcarbonyl (for example, benzyloxycarbonyl), trityl, phthaloyl,etc. A substituent on each of the groups listed above may be a halogenatom (for example, fluorine, chlorine, bromine and iodine, etc.), a C₁₋₆alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl andbutylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3times.

[0541] A protective group for a carboxyl group may for example be anoptionally substituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl,i-propyl, n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc. Asubstituent on each of the groups listed above may be a halogen atom(for example, fluorine, chlorine, bromine and iodine, etc.), a C₁₋₆alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl andbutylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3times.

[0542] A protective group for a hydroxyl group may for example be anoptionally substituted C₁₋₆ alkyl (for example, methyl, ethyl, n-propyl,i-propyl, n-butyl and tert-butyl, etc.), phenyl, a C₇₋₁₀ aralkyl (forexample, benzyl, etc.), a C₁₋₆ alkylcarbonyl (for example, formyl,methylcarbonyl and ethylcarbonyl, etc.), phenyloxycarbonyl (for example,benzoxycarbonyl, etc.), C₇₋₁₀ aralkylcarbonyl (for example,benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. A substituent oneach of the groups listed above may be a halogen atom (for example,fluorine, chlorine, bromine and iodine, etc.), a C₁₋₆ alkyl, phenyl, aC₇₋₁₀ aralkyl, nitro, etc., which may occur 1 to about 4 times.

[0543] A method for cleaving a protective group is a method known per seor an analogous method, such as a treatment for example with an acid, abase, a reduction, UV light, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,etc.

[0544] Compound (I) or a salt thereof according to the invention has anexcellent MMP inhibiting effect, especially an MMP-13 inhibiting effect.

[0545] In addition, compound (I) or a salt thereof according to theinvention has low toxicity and is safe.

[0546] Accordingly, compound (I) or a salt thereof according to theinvention having an excellent MMP inhibiting effect, especially anMMP-13 inhibiting effect, is useful as a safe prophylactic andtherapeutic agent in a mammal (for example, mouse, rat, hamster, rabbit,cat, dog, cattle, sheep, monkey and human) against osteoarthritis,rheumatoid arthritis, osteoporosis, cancer, periodontosis, cornealulcer, pathologic bone resorption (such as Behcet's disease), nephritis,arteriosclerosis, pulmonary emphysema, cirrhosis, autoimmune disease(Crohn's disease and Sjogren's disease), cancer metastasis,contraception, etc.

[0547] A formulation containing compound (I) or a salt thereof accordingto the invention may be in various dosage forms such as a solid formincluding powder, granule, tablet, capsule, etc., and a liquid formincluding syrup, emulsion or solution for injection, etc.

[0548] A prophylactic and therapeutic formulation according to theinvention can be produced by a customary method such as mixing,kneading, granulation, compaction, coating, sterilization andemulsifying depending on the type of the formulation. The production ofa formulation may be in accordance for example with each section in theGeneral Rule of the Formulation under Japanese Pharmacopeia.

[0549] While the amount of compound (I) or a salt thereof in aformulation according to the invention may vary depending on the type ofthe formulation, it is usually 0.01 to 100% by weight, preferably 0.1 to50% by weight, more preferably 0.5 to 20% by weight based on the totalweight of the formulation.

[0550] When compound (I) or a salt thereof is used as a pharmaceuticaldescribed above, it may be used as it is or is treated by a standardmethod if necessary with a pharmaceutically acceptable carrier such asan excipient (for example, starch, lactose, sugar, calcium carbonate andcalcium phosphate), a binder (for example, starch, gum arabic,carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,alginic acid, gelatin and polyvinylpyrrolidone), a lubricant (forexample, stearic acid, magnesium stearate, calcium stearate and talc), adisintegrant (for example, calcium carboxymethyl cellulose and talc), adiluent (for example, water for injection and physiological saline)together with appropriate additives (stabilizer, preservative, colorant,flavor, solubilizing agent, emulsifier, buffer, osmotic agent), andadministered orally or parenterally in a solid dosage form such aspowder, fine powder, granule, tablet, capsule and the like, as well as aliquid form such as an injection formulation. While the dose may varydepending on the types of compound (I) or a pharmaceutically acceptablesalt thereof, the administration route, the condition and the age of apatient, a preferred daily dose per kg body weight as compound (I) or asalt thereof is about 0.005 to 50 mg, preferably about 0.05 to 10 mg,more preferably about 0.2 to 4 mg, which may be divided into 1 to 3times a day.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE

[0551] The present invention is further described in detail in thefollowing Examples and Comparatives, which are not intended to restrictthe invention and may be modified without departing from the scope ofthe invention.

[0552] An elution in column chromatography in each Example was performedunder the observation by a TLC (thin layer chromatography) unlessotherwise specified. In a TLC observation, a 60 F₂₅₄ from Merck wasemployed as a TLC plate. A detection was made by an UV detector or bymeans of a color development with a phosphomolybdic acid. As silica gelfor column chromatography, silica gel 60 (70 to 230 mesh size) fromMerck was employed. As preparative TLC plate, a 60 F₂₅₄ from Merck wasemployed. As a column for high performance liquid chromatography, a YMCPack ODS SH-343-5 or a YMC Pack ODS S-363 I-15 (YMC) was employed. Aroom temperature referred herein means a temperature from 10° C. to 35°C.

[0553] NMR (Nuclear Magnetic Resonance) spectra were measured using a*VARIAN* model Gemini-200 spectrometer (¹H-NMR: 200 MHz) or a *BRUKER*model DPX-300 spectrometer (¹H-NMR: 300 MHz). An internal standard wastetramethylsilane and all δ values are represented in ppm. Abbreviationsemployed here are described below. CDCl₃: deutero chloroform, DMSO-d₆:deutero dimethylsulfoxide, Hz: Herz, J: Coupling constant, m: Multiplet,q: Quartet, t: Triplet, d: Doublet, s: Singlet, br: Broad, dd: Doubledoublet, dq: Double quartet.

Example 1 3-Mercapto-1-(4-phenoxybenzylpyrrolidine-2,5-dione

[0554] 0.50 g (2.1 mmol) of 4-phenoxybenzylamine hydrochloride wasdissolved in 50 ml of chloroform, and washed with a saturated aqueoussodium hydrogen carbonate. After drying over anhydrous magnesiumsulfate, chloroform was concentrated under reduced pressure to obtain aresidue which was treated with 50 ml of toluene and 0.38 g (2.6 mmol) ofthiomalic acid and then heated under reflux with dehydration for 5hours. After concentrating toluene, the residue was treated with 50 mlof acetic acid and heated under reflux overnight, and then the reactionmixture was concentrated to obtain a residue which was subjected tocolumn chromatography on silica gel using chloroform as an eluent, andthe effluent was concentrated into dryness to obtain 0.21 g (yield: 32%)of 3-mercapto-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as a colorlessoil.

[0555]¹H-NMR (200 MHz, CDCl₃)

[0556] δ: 7.40-6.90 (9H, m), 4.70 (1H, d, J=14.0 Hz), 4.58 (1H d, J=14.0Hz), 3.95-3.86 (1H, m), 3.17 (1H, dd, J=18.6, 9.0 Hz), 2.57 (1H, dd,J=18.6, 4.2 Hz), 2.56 (1H, d, J=4.6 Hz)

Example 2 3-Ethylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0557] (1) 5.90 g (29.6 mmol) of 4-phenoxybenzylamine and 2.94 g (30mmol) of maleic anhydride were dissolved in 50 ml of acetic acid andstirred at 130° C. overnight. The reaction mixture was concentrated toobtain a residue which was subjected to column chromatography on silicagel using chloroform as an eluent, and the effluent was concentrated,into dryness to obtain 2.60 g (yield: 32%) of 4-phenoxybenzylmaleimideas a white powder.

[0558]¹H-NMR (200 MHz, CDCl₃)

[0559] δ: 7.40-6.90 (9H, m), 6.71 (2H, s), 4.65 (2H, s)

[0560] (2) 0.10 g (0.36 mmol) of 4-phenoxybenzylmaleimide was dissolvedin 10 ml of ethanol, treated with 0.040 g (0.43 mmol) of ethylmercaptanand stirred at room temperature for 4 hours. The reaction mixture wasconcentrated to obtain a residue which was subjected to columnchromatography on silica gel using chloroform as an eluent, and theeffluent was concentrated into dryness to obtain 0.10 g (yield: 82%) of3-ethylthio-1-(4-phenoxybenzylpyrrolidine-2,5-dione as a colorless oil.

[0561]¹H-NMR (200 MHz, CDCl₃)

[0562] δ: 7.40-6.90 (9H, m), 4.68 (1H, d, J=14. Hz), 4.60 (1H, d, J=14.0Hz), 3.75 (1H, dd, J=9.0, 3.7 Hz), 3.15 (1H, dd, J=18.0, 9.0 Hz),2.95-2.65 (2H, m), 2.54 (1H dd, J=18.0, 3.7 Hz), 1.29 (3H, t, J=7.4 Hz)

Example 33-[2-(Ethoxycarbonyl)ethylthio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0563] By a method similar to that in Example 2, starting from 0.10 g(0.36 mmol) of4-phenoxybenzylmaleimide and 0.06 g (0.43 mmol) of ethyl3-mercaptopropionate, 0.14 g (yield: 95%) of3-[2-(ethoxycarbonyl)ethylthio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dionewas obtained as a colorless oil.

[0564]¹H-NMR (200 MHz, CDCl₃)

[0565] δ: 7.40-6.90 (9H, m), 4.68 (1H, d, J=14.0 Hz), 4.60 (1H, d,J=14.0 Hz), 4.16 (2H, q, J=7.1 Hz), 3.80 (1H, dd, J=10.0, 3.8 Hz),3.26-2.94 (3H, m), 2.68 (2H, t, J=6.0 Hz), 2.51 (1H, dd, J=18.0, 4.0Hz), 1.26 (3H, t, J=7.2 Hz)

Example 4 3-Benzylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0566] By a method similar to that in Example 2, starting from 0.28 g(1.0 mmol) of 4-phenoxybenzylmaleimide and 0.12 g (1.0 mmol) ofbenzylmercaptan 0.42 g of 3benzylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione was obtained almostquantitatively as a colorless oil.

[0567]¹H-NMR (300 MHz, CDCl₃)

[0568] δ: 7.39-7.25 (9H, m), 7.10 (1H, m), 7.02-6.91 (4H, m), 4.66 (1H,d, J=14.1 Hz), 4.60 (1H, d, J=14.1 Hz), 4.20 (1H, d, J=13.5 Hz), 3.84(1H, d, J=13.5 Hz), 3.51 (1H, dd, J=9.2, 3.8 Hz), 2.97 (1H, dd, J=18.8,9.2 Hz), 2.41 (1H, dd, J=18.8, 3.8 Hz)

Example 5 3-Acetylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0569] 1.00 g (5.70 mmol, Aldrich) of S-acetylmercaptosuccinic anhydridewas dissolved in 30 ml of acetic acid, treated with 1.20 g (5.70 mmol)of 4-phenoxybenzylamine hydrochloride and 795 μl (5.70 mmol) oftriethylamine, and then heated at 100° C. for 14 hours with stirring.The reaction mixture was concentrated under reduced pressure to obtain aresidue which was purified three times by column chromatography onsilica gel (eluent: ethyl acetate:hexane (20:8.0), chloroform and ethylacetate:hexane (20:80)) to obtain an intended fraction which was thenconcentrated under reduced pressure to obtain 0.80 g (yield: 40%) of3-acetylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as a yellow oil.

[0570]¹H-NMR (300 MHz, CDCl₃)

[0571] δ: 7.37 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=7.6 Hz), 7.11 (1H, t,J=7.6 Hz), 7.00 (2H, d, J=8.5 Hz), 6.94 (2H, d, J=8.5 Hz), 4.72 (11, d,J=14.1 Hz), 4.65 (1H, d, J=14.1 Hz), 4.23 (1H, dd, J=9.6, 5.6 Hz), 3.25(1H, dd, J=18.5, 9.6 Hz), 2.72 (1H, dd, J=18.5, 5.6 Hz), 2.39 (3H, s)

Example 6 3-Benzoylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0572] By a method similar to that in Example 2, starting from 1.00 g(3.60 mmol) of 4-phenoxybenzylmaleimide and 0.50 g (3.60 mmol) ofthiobenzoic acid, 0.87 g (yield: 58%) of3-benzoylthio-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione was obtained as awhite powder.

[0573]¹H-NMR (300 MHz, CDCl3).

[0574] δ: 7.91 (2H, d, J=7.4 Hz), 7.62 (1H, dd, J=7.6, 7.6 Hz), 7.47(2H, dd, J=7.7, 7.6 Hz), 7.41 (2H, d, J=8.5 Hz), 7.33 (2H, dd, J=7.7,7.6 Hz), 7.11 (1H, dd, J=7.6, 7.4 Hz), 7.01 (2H, d, J=8.5 Hz), 6.95 (2H,d, J=8.5 Hz), 4.78 (1H, d, J=14.1 Hz), 4.70 (1H, d, J=14.1 Hz), 4.41(1H, dd, J=9.5, 5.5 Hz), 3.34 (]I, dd, J=18.5, 9.5 Hz), 2.84 (1H, dd,J=18.5, 5.5 Hz)

Example 7 3-Acetylthio-4-methyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0575] (1) 3.00 g of 2-amino-3-methylsuccinic acid (Sigma, 20.4 mmol)was dissolved in 163 ml of 2.5 N hydrobromic acid, cooled to −10° C.,treated with 7.28 g (61.2 mmol) of potassium bromide, treated with 3.52g (51.0 mmol) of sodium nitrite with stirring over a period of 1.5hours, and then stirred at −5° C. for further 1.5 hours. After addingsodium chloride, the mixture was extracted five times with ethyl acetateand dried over anhydrous sodium sulfate. After concentrating intodryness, the residue was dissolved in 100 ml of ethanol, treated with1.00 ml of concentrated sulfuric acid, and heated under reflux for 10hours. After concentrating, the residue was dissolved in ethyl acetateand washed with saturated aqueous sodium hydrogen carbonate, water andsaturated brine, and then dried over anhydrous sodium sulfate. Afterconcentrating, the residue was subjected to column chromatography onsilica gel using hexane:ethyl acetate (95:5) as an eluent and theeffluent was concentrated to obtain 4.53 g (yield: 83%) diethyl2-bromo-3-methylsuccinate as a colorless oil.

[0576]¹H-NMR (300 MHz, CDCl₃)

[0577] δ: 4.44 (1H, d, J=9.4 Hz), 4.23 (2H, m), 4.16 (2H, q, J=7.2 Hz),3.12 (1H, dq, J=9.4, 7.2 Hz), 1.40 (311 d, J=7.2 Hz), 1.29 (3H, t, J=7.2Hz), 1.25 (3H, t, J=7.2 Hz)

[0578] (2) 2.27 g (8.49 mmol) of diethyl 2-bromo-3-methylsuccinate wasdissolved in 110 ml of ethanol, treated with 1.45 g (12.7 mmol) ofpotassium thioacetate, and stirred at 50° C. for 2 hours, and 0.49 g(4.25 mmol) of potassium thioacetate was further-added and the mixturewas stirred at 50° C. for 1 huir; The reaction mixture was concentrated,dissolved in ethyl acetate, washed with water and saturated brine anddried over anhydrous sodium sulfate. After concentrating, the residuewas subjected to column chromatography on silica gel using hexane:ethylacetate (90:10-80:20) as an eluent, and the effluent was concentratedinto dryness to obtain 1.80 g (yield: 80%) of diethyl2-acethylthio-3-methylsuccinate as a colorless oil.

[0579]¹H-NMR (300 MHz, CDCl)

[0580] δ: 4.56 (1H, d, J=5.7 Hz), 4.17 (4H, n), 3.24 (1H, dq, J=5.7, 7.2Hz), 2.39 (3H, s), 1.26 (3H, t, J=7.2 Hz), 1.26 (3H, d, J=7.2 Hz), 1.26(3H, t, J=7.2 Hz)

[0581] (3) 1.80 g (6.86 mmol) of diethyl 2-acethylthio-3-methylsuccinatewas dissolved in 20.0 ml of acetic acid and 20.0 ml of conc.hydrochloric acid, and stirred at 100° C. for 1.5 hours. The reactionmixture was concentrated, treated with toluene, concentrated,precipitated from ether-hexane to obtain 1.00 g (yield: 89%) of2-mercapto-3-methylsuccinic acid as a white powder.

[0582]¹H-NMR (300 MHz, DMSO-d₆)

[0583] δ: 3.42 (1H, m), 3.13 (1H, m), 2.71 (1H, m), 1.15 (3H, d, J=7.2Hz)

[0584] (4) 0.950 g (5.79 mmol) of 2-mercapto-3-methylsuccinic acid wasdissolved in 15.0 ml of acetic anhydride and stirred at 100° C. for 1hour. The reaction mixture was concentrated, treated with toluene,concentrated into dryness to obtain 0.963 g (yield: 88%) of3-acetylthio-4-methylsuccinic anhydride as a colorless oil.

[0585]¹H-NMR (300 MHz, CDCl₃)

[0586] δ: 3.93 (1H, d, J=8.3 Hz), 3.17 (1H, m), 2.44 (3H, s), 1.49 (3H,d, J=7.2 Hz)

[0587] (5) 0.930 g (4.90 mmol) of 3-acetylthio-4-methylsuccinicanhydride was dissolved in 25.0 ml of dichloromethane, and 1.16 g (4.94mmol) of 4-phenoxybenzylamine hydrochloride and 1.03 ml (7.41 mmol) oftriethylamine were added and the mixture was stirred at room temperaturefor 2 hours and then the reaction mixture was concentrated into dryness.The residue was dissolved in 15.0 ml of acetic anhydride, treated with1.00 g of sodium acetate, and then stirred at 100° C. for 20 minutes.After concentrating the reaction mixture, the residue was dissolved inethyl acetate, washed with water and saturated brine, and then driedover anhydrous sodium sulfate. After concentrating, the residue wassubjected to column chromatography on silica gel using hexane:ethylacetate (75:25) as an eluent, and the effluent was concentrated intodryness to obtain 0.491 g (yield: 27%) of3-acethylthio-4-methyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as acolorless oil.

[0588]¹H-NMR (300 MHz, CDCl₃)

[0589] δ: 7.35 (4H, m), 7.11 (1H, m), 7.00 (2H, m), 6.94 (2H, d, J=8.7Hz), 4.72 (1H, d, J=14.1 Hz), 4.63 (1H, d, J=14.1 Hz), 3.85 (1H, d,J=6.4 Hz), 2.85 (1H, m), 2.40 (3H, s), 1.40 (3H, d, J=7.2 Hz)

Example 8 3-Mercapto-4-methyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0590] 0.360 g (0.974 mmol) of3-acethylthio-4-methyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione obtainedin Example 7 was dissolved in 20 ml of acetic acid and 10.0 ml of conc.hydrochloric acid, and stirred at 100° C. for 30 minutes. The reactionmixture was treated with toluene and concentrated into dryness to obtaina residue, which was then subjected to column chromatography on silicagel using hexane:ethyl acetate (80:20) as an eluent, and the effluentwas concentrated into dryness to obtain 0.208 g (yield: 65%) of3-mercapto-4-methyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as acolorless oil.

[0591]¹H-NMR (300 MHz, CDCl₃)

[0592] δ 7.33 (4H, m), 7.11 (1H, m), 7.00 (2H, m), 6.93 (2H, d, J=8.3Hz), 4.67 (1H, d, J=13.9 Hz), 4.61 (1H, d, J=13.9 Hz), 3.48 (1H, dd,J=5.3, 5.3 Hz), 2.67 (1H, dq, J=5.3, 7.2 Hz), 2.44 (1H, d, J=5.3 Hz),1.41 (3H, d, J=7.2 Hz)

Example 93-Hydroxy-4-[2-(methoxycarbonyl)ethylthio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0593] (1) 10.0 g (75.7 mmol, TOKYO KASEI KOGYO) of cis-epoxysuccinicacid was dissolved in 200 ml of ethanol and treated with 2.00 ml ofconc. sulfuric acid and heated under reflux for 4 hours. The reactionmixture was concentrated, dissolved in ethyl acetate, and washed withwater and saturated brine. After drying over anhydrous sodium sulfatefollowed by concentrating into dryness, 13.5 g (yield: 95%) of adiethylester product was obtained as a colorless oil.

[0594]¹H-NMR (300 MHz, CDCl₃)

[0595] δ: 4.27 (4H, q, J=7.2 Hz), 3.70 (2H, s), 1.31 (6H, t, J=7.2 Hz)

[0596] (2) 4.00 g (21.30 mmol) of the diethylester product thus obtainedwas dissolved in 200 ml of ethanol, treated with 21.30 ml (21.30 mmol)of a 1N aqueous solution of sodium hydroxide and then stirred at roomtemperature for 2 hours. The reaction mixture was concentrated, treatedwith saturated brine, adjusted at pH 2.0 with 1N hydrochloric acid, andthen extracted five times with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated into dryness to obtain 1.92 g (yield: 56%) ofethylhydrogen-cis-epoxysuccinic acid as a colorless oil.

[0597]¹H-NMR (300 MHz, CDCl ₃)

[0598] δ: 4.32 (2H, m), 3.80 (1H, d, J=4.5 Hz), 3.76 (1H, d, J=4.9 Hz),1.33 (3H, t, J=7.2 Hz)

[0599] (3) 0.679 g (4.24 mmol) of ethylhydrogen-cis-epoxysuccinic acidwas dissolved in 20.0 ml of N,N-dimethylformamide, and then 0.845 g(4.24 mmol) of 4-phenoxybenzylamine, 0.634 ml (4.24 mmol) of diethylcyanomalate and 0.591 ml (4.24 mmol) of triethylamine were added and themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated, dissolved in ethyl acetate, washed with 10%aqueous citric acid, saturated aqueous sodium hydrogen carbonate, waterand saturated brine and then dried over anhydrous sodium sulfate. Afterconcentrating, the residue was subjected to column chromatography onsilica gel using hexane:ethyl acetate (70:30) as an eluent, and theeffluent was concentrated into dryness to obtain 0.870 g (yield: 60%) ofethyl-cis-3-(4-phenoxybenzylcarbamoyl)-2-oxylane-carboxylate as acolorless oil.

[0600]¹H-NMR (300 MHz, CDCl₃)

[0601] δ: 7.34 (2H, m), 7.25 (2H, d, J=8.5 Hz), 7.11 (1H, m), 6.98 (4H,m), 6.77 (1H, m), 4.45 (1H dd, j=14.7, 6.4 Hz), 4.35 (1H, dd, J=14.7,5.7 Hz), 4.16 (2 Hz q, J=7.2 Hz), 3.74 (1H, d, j=4.9 Hz), 3.72 (1H, d,J=4.9 Hz), 1.25 (3H, t, J=7.2 Hz)

[0602] (4) 0.770 g (2.26 mmol) ofethyl-cis-3-(4-phenoxybenzylcarbamoyl)-2-oxylane-carboxylate wasdissolved in 30 ml of methanol, treated with 2.49 ml (2.49 mmol) of a 1Naqueous solution of sodium hydroxide and stirred at room temperature for2 hours. The reaction mixture was adjusted at pH 2.0, concentrated,diluted with ethyl acetate, and washed with water and saturated brine.After drying over anhydrous sodium sulfate followed by concentratinginto dryness, 0.650 g (yield: 92%) ofcis-3-(4-phenoxybenzylcarbamoyl)-2-oxylanecarboxylic acid was obtainedas a white powder.

[0603]¹H-NMR (300 MHz, DMSO-d₆)

[0604] δ: 8.54 (1H, m), 7.38 (2H, m), 7.27 (2H, d, J=8.3 Hz), 7.13 (1H,m), 6.98 (2H, m), 6.94 (2H, d, J=8.3 Hz), 4.29 (1H, dd, J=15.1, 6.4 Hz),4.23 (1H, dd, J=15.1, 5.7 Hz), 3.79 (1H, d, J=4.9 Hz), 3.76 (1H, d,J=4.9 Hz)

[0605] (5) 0.250 g (0.80 mmol) ofcis-3-(4-phenoxybenzylcarbamoyl)-2-oxylanecarboxylic acid was dissolvedin 5.00 ml of acetic anhydride, treated with 0.250 g of sodium acetate,and stirred at 120° C. for 5 minutes. The reaction mixture wasconcentrated, dissolved in ethyl acetate, washed with water andsaturated brine, and then dried over anhydrous sodium sulfate. Afterconcentrating, the residue was subjected to column chromatography onsilica gel using hexane:ethyl acetate-(−70:30-60:40) as an eluent, andthe effluent was concentrated and precipitated from hexane-ethyl acetateto obtain 0.129 g (yield: 55%) of3,4-epoxy-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as a white powder.

[0606]¹H-NMR (300 MHz, CDCl₃)

[0607] δ: 7.33 (2H, m), 7.26 (2H, d, J=8.3 Hz), 7.11 (1H, m), 6.99 (2H,m), 6.93 (2H, d, J=8.7 Hz), 4.54 (2H, s), 4.05 (2H, s)

[0608] (6) 0.220 g (0.740 mmol) of3,4-epoxy-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione was dissolved in 10.0ml of N,N-dimethylformamide, treated with 0.309 g (2.24 mmol) ofpotassium carbonate and 0.248 ml (2.24 mmol) of methyl3-mercaptopropionate, and then stirred at room temperature for 10minutes. After adding 3N hydrochloric acid, the mixture was extractedtwice with ethyl acetate. The ethyl acetate layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating, the residue was subjected to column chromatography onsilica gel using hexane:ethyl acetate (50:50) as an eluent, and theeffluent was concentrated into dryness to obtain 0.153 g (yield: 49%) of3-hydroxy-4-[2-(methoxycarbonyl)ethylthio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dioneas a colorless oil.

[0609]¹H-NMR (300 MHz, CDCl₃)

[0610] δ: 7.34 (4H, m), 7.12 (1H, m), 7.00 (2H, m), 6.93 (2H, d, J=8.3Hz), 4.67 (1H, d, J=14.1 Hz), 4.63 (1H, d, J=14.1 Hz), 4.46 (1H, m),3.78 (1H, d, J=5.3 Hz), 3.71 (3H, s), 3.48 (1H, d, J=3.0 Hz), 3.09 (2H,m), 2.75 (2H, t, J=7.0 Hz)

Example 10 3-Acethylmethyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0611] 1.90 g (8.90 mmol) of 4-phenoxybenzylamine hydrochloride wasdissolved in ethyl acetate, and washed with saturated aqueous sodiumcarbonate. The organic layer was concentrated under reduced pressure,dissolved in 100 ml of toluene, treated with 1.00 g (8.90 mmol) ofitaconic anhydride, and stirred at room temperature for 4 hours. 2.50 ml(19.8 mmol) of triethylamine and 1.30 ml (19.8 mmol) of thioacetic acidwere added, and the mixture was stirred for further 16 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, dissolved in ethyl acetate, washed twice with water, dilutehydrochloric acid, water and then saturated brine, and the organic layerwas dried over anhydrous sodium sulfate. After concentrating underreduced pressure, the residue was subjected to column chromatography onsilica gel, and the fraction eluted with ethyl acetate:hexane(10:90-50:50) was concentrated, dissolved in 50 ml of toluene, treatedwith 10 ml of acetic anhydride, and then stirred with heating at 100° C.for 3 hours. The reaction mixture was concentrated under reducedpressure and the residue was subjected to column chromatography onsilica gel, and the fraction eluted with ethyl acetate:hexane(20:80-30:70) was purified again by high pressure liquid chromatography(eluent: 60% acetonitrile/0.05% trifluoroacetic acid). Desired fractionswere concentrated under reduced pressure, extracted twice with ethylacetate, and the organic layer obtained was washed with saturated brineand dried over anhydrous sodium sulfate. This solution was concentratedunder reduced pressure to obtain 0.536 g (yield: 16%) of3-acethylmethyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as a tan oil.

[0612]¹H-NMR (300 MHz, CDCl₃)

[0613] δ: 7.33 (4H, m), 7.11 (1H, t, J=7.4 Hz), 6.99 (2H, d, J=7.7 Hz),6.93 (2H, d, J=8.6 Hz), 4.65 (1H, d, J=14.1 Hz), 4.59 (1H, d, J=14.1Hz), 3.42 (1H, dd, J=13.4, 4.1 Hz), 3.25-3.09 (2H, m), 2.83 (1H, dd,J=18.4, 8.8 Hz), 2.45 (1H, dd, J=18.4, 4.8 Hz), 2.34 (3H, s)

Example 113-[(Tetrahydro-2-furanyl)methyldithio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0614] 5.00 g (30.0 mmol) of tetrahydrofurfuryl bromide was dissolved in30 ml of ethanol, and 2.30 g (30.0 mmol) of thiourea was added and themixture was heated under reflux for 16 hours. The reaction mixture wasconcentrated under reduced pressure, and then dissolved in 30 ml of a 1Naqueous solution of sodium hydroxide and heated at 100° C. for 1.5hours. After cooling and extracting with ethyl acetate, the organiclayer was washed with water and saturated brine, and then dried overanhydrous sodium sulfate. This solution was concentrated under reducedpressure to obtain 0.208 g of a tan oil. The oil thus obtained wasdissolved in 20 ml of methanol, and treated with 0.552 g (1.80 mmol) of3-mercapto-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione obtained in Example1, 0.178 g (1.80 mmol) of triethylamine and excessive iodine, and thenstirred at room temperature for 1 hour. After concentrating underreduced pressure, the residue was dissolved in ethyl acetate, washedwith water, an aqueous solution of sodium thiosulfate and saturatedbrine, and then dried over anhydrous sodium sulfate. After concentratingunder reduced pressure, the residue was purified three times by columnchromatography on silica gel (eluent: ethyl acetate:hexane(30:70-50:50), chloroform and ethyl acetate:hexane (20:80)) followed byhigh pressure liquid chromatography (eluent: 60% acetonitrile/0.05%trifluoroacetic acid) for a further purification. Desired fractions wereconcentrated under reduced pressure and extracted twice with ethylacetate, and the organic layers obtained were combined and washed withsaturated aqueous sodium hydrogen carbonate and saturated brine, andthen dried over anhydrous sodium sulfate. This solution was concentratedunder reduced pressure to obtain 0.045 g (yield 6%) of3-[(tetrahydro-2-furanyl)methyldithio]-1-(4-phenoxybenzyl)pyrrolidine-2,5-dioneas a tan oil.

[0615]¹H—NMR (300 MHz, CDCl₃)

[0616] δ: 7.38-(2H d, J=8.5 Hz), 7.31 (2H, d, J=7.9 Hz), 7.11 (1H, m),6.99 (2H, d, J=7.9 Hz), 6.93 (2H, d, J=8.5 Hz), 4.70 (0.5H, d, J=14.0Hz), 4.69 (0.5H, d, J=14.0 Hz), 4.63 (0.5H, d, J=14.0 Hz), 4.62 (0.5H,d, J=14.0 Hz), 4.09-3.68 (4H, m), 3.17 (0.5H, dd, J=18.8, 2.6 Hz), 3.14(0.5H, dd, J=18.8, 2.7 Hz), 2.95 (0.5H, dd, J=18.8, 4.2 Hz), 2.92 (0.5H,dd, J=18.8, 4.2 Hz), 2.81 (0.5H, dd, J=13.4, 6.7 Hz), 2.67 (1H, m), 2.52(0.5H, dd, J=13.4, 7.4 Hz), 2.06-1.82 (3H, m), 1.61-1.43 (1H, m)

Example 12 3,3′-Dithiobis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione

[0617] 0.100 g (0.35 mmol) of3-mercapto-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione obtained in Example1 was dissolved in 100 ml of ethanol and treated with 0.15 g (0.60 mmol)of iodine and then allowed to stand at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure and purified bya high pressure liquid chromatography (eluent: 60% acetonitrile/0.01 Mphosphate buffer (pH 6.3)). Desired fractions were concentrated underreduced pressure, extracted twice with ethyl acetate, and the organicphase obtained was washed with saturated brine, and dried over anhydroussodium sulfate. This solution was concentrated under reduced pressure toobtain 0.062 g (yield: 31%) of3,3′-dithiobis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione as a whitepowder.

[0618]¹H-NMR (300 MHz, CDCl₃)

[0619] δ: 7.33 (8H, m), 7.11 (2H, td, J=7.6, 2.6 Hz), 6.95 (8H, m), 4.63(4H, brs.), 4.02 (1H, dd, J=9.2, 4.8 Hz), 3.82 (1H, dd, J=9.1, 4.6 Hz),3.13 (1H, dd, J=18.9, 9.1 Hz), 3.03 (1H, dd, J=18.8, 9.2 Hz), 2.86 (1H,dd, J=18.9, 4.6 Hz), 2.74 (1H, dd, J=18.8, 4.8 Hz)

Example 133,3′-[Dithiobis(methylene)]bis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione]

[0620] 0.300 g (0.80 mmol) of3-acethylmethyl-1-(4-phenoxybenzyl)pyrrolidine-2,5-dione obtained inExample 10 was dissolved in 3 ml of methanol, and 3 ml of a 28% solutionof sodium methoxide in methanol was added and the mixture was stirred atroom temperature for 20 minutes. The reaction mixture was made acidicwith 1N hydrochloric acid, and then treated further with water. Themixture was extracted twice with ethyl acetate, and the organic phaseobtained was washed with saturated aqueous sodium carbonate andsaturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was subjected tocolumn chromatography on silica gel, and the fraction eluted with ethylacetate:hexane (50:50) was concentrated under reduced pressure to obtain0.059 g (yield: 20%) of3,3′-[dithiobis(methylene)]bis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione]as a colorless oil.

[0621]¹H-NMR (300 MHz, CDCl₃)

[0622] δ: 7.33 (8H, t, J=8.5 Hz), 7.10 (2H, t, J=7.5 Hz), 6.99 (4H, d,J=8.6 Hz), 6.92 (4H, d, J=8.6 Hz), 4.63 (2H, s), 4.62 (2H, s), 3.10-2.74(8H, m), 2.59 (1H, dd, J=18.3, 5.0 Hz), 2.53 (1H, dd, J=18.3, 5.0 Hz)

Example 14 3,3′-[Thiobis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione]

[0623] 1.00 g (4.20 mmol) of 4-phenoxybenzylamine hydrochloride wasdissolved in ethyl acetate, and washed with saturated aqueous sodiumhydrogen carbonate. The organic layer was concentrated under reducedpressure, dissolved in 50 ml of toluene, treated with 0.506 g (1.90mmol, TOKYO KASEI) of thiodisuccinic acid, and heated under reflux for 4hours with dehydrating. The reaction mixture was concentrated underreduced pressure, dissolved in ethyl acetate, washed with water andsaturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating, the residue was subjected to column chromatography onsilica gel, and the fraction eluted with ethyl acetate:hexane(20:80-30:70) was concentrated under reduced pressure to obtain 0.180 g(yield: 8%) of 3,3′-[thiobis[1-(4-phenoxybenzyl)pyrrolidine-2,5-dione]as a yellow oil.

[0624]¹H—NMR (300 MHz, CDCl₃)

[0625] δ: 7.33 (8H, m), 7.11 (2H, m), 6.95 (8H, m), 4.64 (4H, brs), 4.61(1H, dd, J=9.3, 4.3 Hz), 4.08 (1H, dd, J=9.3, 4.3 Hz), 3.16 (2H, dd,J=18.8, 9.3 Hz), 2.71 (1H, dd, J=18.8, 4.3 Hz), 2.43 (1H, dd, J=18.8,4.3 Hz)

Example 15 4-Acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0626] (1) 2.79 g (20.0 mmol) of glycine ethyl ester hydrochloride wasdissolved in 30 ml of methanol, 3.23 g (20.0 mmol) of triethylamine wasadded and the mixture was stirred at room temperature for 10 minutes,and then 3.96 g (20.0 mmol) of 4-phenoxybenzaldehyde was added and themixture was stirred for 5 hours. 0.378 g (10.0 mmol) of sodiumborohydride was added in portions and the mixture was stirred at roomtemperature for 2 hours, and then the reaction mixture was concentrated,treated with saturated aqueous sodium hydrogen carbonate, and extractedwith ethyl acetate. The ethyl acetate layer was washed with water,concentrated to obtain a residue which was then treated with 50 ml ofether and 10 ml of a 4N solution of hydrogen chloride in ethyl acetateand then stirred at room temperature for 30 minutes. The precipitate wascollected by filtration, and washed with ether to obtain 5.49 g (yield:85%) of a hydrochloride of a reduced amino product as a white powder.

[0627]¹H—NMR (200 MHz, DMSO-d₆)

[0628] δ: 10.2-9.6 (1H, m), 7.62-6.97 (9H, m), 4.30-4.10 (4H, m),4.00-3.82 (2H, m), 1.23 (3H, t, J=7.1 Hz)

[0629] (2) 5.00 g (16.0 mmol) the amine product thus obtained wasdissolved in 50 ml of chloroform, treated with 3.46 g (34.0 mmol) oftriethylamine with cooling on ice, stirred for 10 minutes, treateddropwise with 2.57 g (17.0 mmol) of ethyl malonyl chloride and thenstirred at room temperature overnight. The mixture was made acidic with2N hydrochloric acid and then extracted, and the chloroform layer waswashed with water, concentrated, subjected to column chromatography onsilica gel eluting with hexane:ethyl acetate=70:30) to obtain 3.40 g(yield: 55%) of an amide product as a pale yellow oil.

[0630]¹H-NMR (200 MHz, CDCl₃)

[0631] δ: 7.40-6.90 (9H, m), 4.65 (1H, s), 4.61 (1H, s), 4.27-4.10 (4H,m), 4.06 (1H, s), 3.98 (1H, s), 3.58 (1H, s), 3.48 (1H, s), 1.35-1.20(6H, m)

[0632] (3) 3.40 g (8.51 mmol) of the amide product thus obtained wasdissolved in 30 ml of ethanol, treated with 2.90 ml (8.51 mmol) of a 20%solution of sodium ethoxide in ethanol, and stirred at room temperaturefor 1 hour. The reaction mixture was concentrated at low temperature andthe residue was made acidic with 2N hydrochloric acid and then extractedwith ethyl acetate. The ethyl acetate layer was washed with water andconcentrated at low temperature, and the residue was treated with ethylacetate:hexane (1:5) and stirred for 10 minutes, and then theprecipitate was collected by filtration and washed with the samesolution to obtain 2.34 g (78%) of a pyrrolidin-2-one product as a whitepowder.

[0633]¹H-NMR (200 MHz, CDCl₃)

[0634] δ: 7.40-6.90 (9H, m), 4.57 (2H, s), 4.41 (2H, q, J=7.1 Hz), 3.88(2H, s), 1.41 (3H, t, J=7.1 Hz)

[0635] (4) 0.350 g (1.00 mmol) of the pyrrolidin-2-one product thusobtained was dissolved in 10 ml of acetonitrile, treated with 0.5 ml ofwater and stirred at 90° C. for 30 minutes. The reaction mixture wasconcentrated, treated with 10 ml of methanol, treated with 0.038 g (1.00ml) of sodium borohydride in portions at room temperature and stirredfor 1 hour. The reaction mixture was concentrated, and the residue wastreated with ethyl acetate and saturated aqueous sodium hydrogencarbonate and then extracted. The ethyl acetate layer was washed withwater, concentrated, subjected to column chromatography on silica geleluting with methanol:chloroform (3:97) to obtain 0.280 g (yield: 99%)of an alcohol product as a colorless oil.

[0636]¹H-NMR (200 MHz, CDCl₃)

[0637] δ: 7.40-6.90 (9H, m), 4.57-4.45 (1H, m), 4.45 (2H, s), 3.53 (1H,dd, J=10.7, 5.7 Hz), 3.21 (1H, dd, J=10.7, 2.1 Hz), 2.75 (1H, dd,J=17.4, 6.5 Hz), 2.44 (1H, dd, J=17.4, 2.5 Hz), 2.32-2.24 (1H, m)

[0638] (5) 0.120 g (0.42 mmol) of the alcohol product thus obtained wasdissolved in 10 ml of pyridine, treated with 0.115 g (1.00 mmol) ofmethanesulfonyl chloride and stirred at 50° C. for 2 hours. The reactionmixture was concentrated, and the residue was made acidic with 2Nhydrochloric acid and then extracted with ethyl acetate. The ethylacetate layer was washed with water and concentrated, and the residuewas combine with a mixture of hexane:ethyl acetate (5:1) and stirred for30 minutes. The precipitate was collected by filtration and washed withthe same solution to obtain 0.120 g (yield: 79%) of a mesylate productas a white powder.

[0639]¹H-NMR (200 MHz, CDCl₃)

[0640] δ: 7.40-6.95 (9H, m), 5.35-5.25 (1H, m), 4.47 (2H, brs), 3.67(1H, dd, J=12.0, 5.6 Hz), 3.53 (1H, dd, J=12.0, 2.2 Hz), 3.02 (3H, s),2.89 (1H, dd, J=17.9, 6.7 Hz) 2.71 (1H, dd, J=17.9, 2.7 Hz)

[0641] (6) 0.090g (0.25 mmol) of the mesylate product thus obtained wasdissolved in 5 ml of N,N-dimethylformamide, treated with 0.085 g (0.75mmol) of potassium thioacetate and stirred at 70° C. for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate,and the ethyl acetate layer was washed with water and concentrated toobtain a residue which was subjected to column chromatography on silicagel eluting with hexane:ethyl acetate (60:40) to obtain 0.055 g (yield:64%) of 4-acethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as a whitepowder.

[0642]¹H-NMR (200 MHz, CDCl₃)

[0643] δ: 7.40-6.95 (9H, m), 4.44 (2H, brs), 4.13-3.98 (1H, m), 3.76(1H, dd, J=10.7, 7.5 Hz), 3.17 (1H, dd, J=10.7, 4.9 Hz), 2.92 (1H, dd,J=17.4, 8.9 Hz), 2.42 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s)

Example 16 4-Benzoylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0644] 0.100 g (0.28 mmol) of the mesylaete product obtained in Example15, 0.046 g (0.66 mmol) of thiobenzoic acid and 0.092 g (0.66 mmol) ofpotassium carbonate were dissolved in 10 ml of N,N-dimethylformamide andstirred at 80° C. for 2 hours. The residue was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater and concentrated, and the residue was subjected to columnchromatography on silica gel eluting with hexane:ethyl acetate (70:30)to obtain 0.052 g (yield: 46%) of4-benzoylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as a white powder.

[0645]¹H-NMR (200 MHz, CDCl₃)

[0646] δ: 7.92-6.90 (14H, m), 4.47 (2H, s), 4.33-4.20 (1H, n), 3.88 (1H,dd, J=10.7, 7.5 Hz), 3.29 (1H, dd, J=10.7, 4.8 Hz), 3.03 (1H, dd,J=17.4, 9.0 Hz), 2.56 (1H, dd, J=17.4, 5.9 Hz)

Example 17 4-Mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0647] 25 mg (0.07 mmol) of4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one was dissolved in amixture of 5 ml of acetic acid and 1 ml of conc. hydrochloric acid, andstirred at 100° C. for 2 hours. The reaction mixture was concentrated,and the residue was treated with ethyl acetate and saturated aqueoussodium hydrogen carbonate and extracted. The ethyl acetate layer waswashed with water and concentrated, and the residue was subjected tocolumn chromatography on silica gel eluting with chloroform to obtain 20mg (yield: 95%) of 4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[0648]¹H-NMR (200 MHz, CDCl₃)

[0649] δ: 7.40-6.93 (9H, m), 4.48 (1H, d, J=14.7 Hz), 4.40 (1H, d,J=14.7 Hz), 3.66 (1H, dd, J=9.8, 7.1 Hz), 3.61-3.47 (1H, m), 3.17 (1H,dd, J=9.8, 4.8 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1,6.1 Hz), 1.87 (1H, d, J=6.8 Hz)

Example 18 4-Pivaloyloxymethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0650] 80 mg (0.27 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17was dissolved in 15 ml of chloroform, treated with 11 mg (0.27 mmol) ofsodium hydride (60% in oil) and 41 mg (0.27 mmol) of pivaloyloxymethylchloride, and stirred at room temperature for 1 hour. Water was addedslowly, followed by extraction, and the chloroform layer was washed andconcentrated, and the residue was subjected to column chromatography onsilica gel eluting with hexane:ethyl acetate (70:30) to obtain 63 mg(yield: 78%) of4-pivaloyloxymethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[0651]¹H-NMR (200 MHz, CDCl₃)

[0652] δ 7.40-6.93 (1H, m), 4.48 (1H, d, J=14.8 Hz), 4.39 (1H, d, J=14.8Hz), 4.02-3.90 (1H, m), 3.77 (1H, m), 3.77 (1H, dd, J=10.6, 7.4 Hz),3.13 (1H, dd, J=10.6, 4.6 Hz), 2.93 (1H, dd, J=17.4, 8.9 Hz), 2.43 (1H,dd, J=17.4, 5.8 Hz), 1.20 (9H, s)

Example 19 4,4′-Dithiobis[1-(4-phenoxybenzyl)pyrrolidin-2-one]

[0653] 30 ml of ethyl acetate and 30 ml of water were added to aseparatory funnel, to which 80 mg (0.27 mmol) of4-mercapto-2-(4-phenoxybenzyl)pyrrolidin-2-one, 68 mg (0.27 mmol) ofiodine and 45 mg (0.27 mmol) of potassium iodide were added and shakenat room temperature for 5 minutes. After a partition, the ethyl acetatelayer was washed with an aqueous solution of sodium hydrogen sulfitefollowed by water, and then concentrated into dryness. The residue wasdiluted with hexane and stirred, and the precipitate was collected byfiltration t obtain 63 mg (yield: 78%) of4,4′-dithiobis[1-(4-phenoxybenzyl)piperidin-2-one] as a white powder.

[0654]¹H-NMR (200 MHz, CDCl₃)

[0655] δ: 7.40-6.90 (18H, m), 4.50 (1H, d, J=14.7 Hz), 4.48 (1H, d,J=14.7 Hz), 4.38 (1H, d, J=14.7 Hz), 4.35 (1H, d, J=14.7 Hz), 3.65-3.53(2H, m), 3.53-3.37 (2H, m), 3.31-3.22 (2H, m), 2.85 (1H, dd, J=8.0, 2.9Hz), 2.77 (1H, dd, J=7.8, 3.1 Hz), 2.49 (2H, dd, J=17.6, 4.4 Hz).

Example 20Trans-4-acetylthio-5-hydroxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0656] (1) 13.5 ml (185 mmol) of thionyl chloride was added dropwise to52 ml of methanol with ice-cooling over 30 minutes, 10.0 g (51.2 mmol)of O-benzyl-D,L-serine was added and the mixture was stirred at roomtemperature for 15 hours. The reaction mixture was concentrated, treatedwith toluene, concentrated, treated with methanol, concentrated, treatedwith ether to precipitate, whereby obtaining 12.0 g (yield: 95%) ofO-benzyl-D,L-serine methyl ester hydrochloride as a white powder.

[0657]¹H-NMR (300 MHz, DMSO-d₆)

[0658] δ: 8.71 (3H, s), 7.35 (5H, m), 4.58 (1H, d, J=12.1 Hz), 4.49 (1H,d, J=12.1 Hz), 4.35 (1H, t, J=3.4 Hz), 3.85 (2H d, J=3.4 Hz), 3.74 (3H,s)

[0659] (2) 9.50 g (38.7 mmol) of O-benzyl-D,L-serine methyl esterhydrochloride was dissolved in 160 ml of methanol, treated with 8.09 ml(58.1 mmol) of triethylamine and 6.78 ml (38.7 mmol) of4-phenoxybenzaldehyde, and then stirred at room temperature for 20hours. 1.46 g (38.7 mmol) of sodium borohydride was added and themixture was stirred at room temperature for 2.5 hours. The reactionmixture was concentrated, treated with ethyl acetate, washed with waterand saturated brine, and then dried over anhydrous sodium sulfate. Afterconcentrating followed by column chromatography on silica gel elutingwith hexane ethyl acetate (80:20-60:40) followed by concentrating intodryness, 13.0 g (yield: 86%) of N-(4-phenoxybenzyl)-O-benzyl-D,L-serinemethyl ester as a colorless oil.

[0660]¹H-NMR (300 MHz, CDCl₃)

[0661] δ: 7.30 (9H, m), 7.08 (1H, m), 6.98 (4H, m), 4.54 (1H, d, J=12.4Hz), 4.50 (1H, d, J=12.4 Hz), 3.86 (1H, d, J=12.8 Hz), 3.73 (3H, s),3.70 (3H, m), 3.51 (1H, t, J=4.9 Hz)

[0662] (3) 13.0 g (33.2 mmol) of N-(4-phenoxybenzyl)-O-benzyl-D,L-serinemethyl ester was dissolved in 130 ml of chloroform, treated with 5.55 ml(39.8 mmol) of triethylamine and 5.10 ml (39.8 mmol) of ethyl malonylchloride with cooling on ice, and stirred at room temperature for 1hour. The reaction mixture was concentrated, treated with ethyl acetate,washed with water and saturated brine and then dried over anhydroussodium sulfate. After concentrating followed by column chromatography onsilica gel eluting with hexane:ethyl acetate (70:30-60:40) followed byconcentrating into dryness, 14.3 g (yield: 85%) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-o-benzyl-D,L-serine methyl ester asa colorless oil.

[0663]¹H-NMR (300 MHz, CDCl₃)

[0664] δ: 7.28 (9H, m), 7.12 (1H, m), 6.98 (4H, m), 4.72 (3H, m), 4.41(2H, s), 4.18 (2H, q, J=7.2 Hz), 3.97 (2H, m), 3.71 (3H, s), 3.47 (1H,d, J=15.3 Hz), 3.39 (1H, d, J=15.3 Hz), 1.25 (3H, t, J=7.2 Hz)

[0665] (4) 2.40 g (4.75 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-O-benzyl-D,L-serine methyl esterwas dissolved in 30.0 ml of methanol, treated with 240 mg of 10%Palladium on activated charcoal and 30 ml of conc. hydrochloric acid,and stirred under hydrogen atmosphere at room temperature for 2 hours.After filtrating the catalyst off followed by concentrating intodryness, 1.90 g (yield: 96%) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-serine methyl ester as acolorless oil.

[0666]¹H-NMR (300 MHz, CDCl₃)

[0667] δ: 7.33 (4H, m), 7.13 (1H, m), 7.01 (4H, m), 4.64 (1H, d, J=16.8Hz), 4.58 (1H, d, J=16.8 Hz), 4.21 (2H, q, J=7.2 Hz), 4.13 (2H, m), 3.93(1H, m), 3.72 (3H, s), 3.56 (1H, d, J=15.8 Hz), 3.45 (1H, d, J=15.8 Hz),1.29 (3H, t, J=7.2 Hz)

[0668] (5) 1.90 g (4.57 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-serine methyl ester wasdissolved in 20.0 ml of ethanol, treated with 1.79 ml (4.57 mmol) of a20% solution of sodium ethoxide in ethanol and stirred at roomtemperature for 1 hour. The reaction mixture was concentrated, treatedwith ethyl acetate, washed with 10% aqueous citric acid, water and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thereaction mixture was concentrated and dissolved in 30.0 ml of methanol,159 mg (4.20 mmol) of sodium borohydride was added with stirring, andthen the mixture was stirred further for 1 hour at room temperature.After adding 1N hydrochloric acid followed by extracting twice withethyl acetate, the ethyl acetate layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. Afterconcentrating followed by column chromatography on silica gel elutingwith chloroform:methanol (95:5) followed by concentrating into dryness,520 mg (yield 36%) ofcis-4-hydroxy-5-hydroxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as awhite powder.

[0669]¹H-NMR (300 MHz, CDCl₃)

[0670] δ: 7.34 (2H, m), 7.19 (2H, d, J=8.3 Hz), 7.11 (1H, m), 6.97 (4H,m), 4.97 (1H, d, J=15.1 Hz), 4.61 (1H, m), 4.07 (1H, d, J=15.1 Hz), 3.92(2H, m), 3.55 (1H, m), 3.49 (1H, m), 3.06 (1H, s), 2.76 (1H, dd, J=17.2,7.5 Hz), 2.54 (1H, dd, J=17.2, 4.9 Hz)

[0671] (6) 500 mg (1.60 mmol) ofcis-4-hydroxy-5-hydroxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one wasdissolved in 15.0 ml of chloroform, treated with 491 mg (1.76 mmol) oftrityl chloride, 401 μl (2.88 mmol) of triethylamine and 7.82 mg (0.064mmol) of 4-dimethylaminopyridine, and stirred at room temperature for 9hours. The reaction mixture was concentrated, treated with ethylacetate, washed with water and saturated brine, and dried over anhydroussodium sulfate. After concentrating followed by column chromatography onsilica gel eluting with hexane:ethyl acetate (70:30-60:40) followed byconcentrating into dryness, 700 mg (yield: 79%) ofcis-4-hydroxy-1-(4-phenoxybenzyl)-5-trityloxymethylpyrrolidin-2-one as acolorless oil.

[0672]¹H-NMR (300 MHz CDCl₃)

[0673] δ: 7.33 (19H, m), 7.11 (1H, m), 6.98 (2H, m), 6.87 (2H, d, J=8.3Hz), 4.94 (1H, d, J=14.7 Hz), 4.55 (1H, m), 3.58 (2H, m), 3.47 (1H, dd,J=10.0, 3.4 Hz), 3.40 (1H, dd, J=10.0, 5.7 Hz), 2.77 (1H, dd, J=17.3,7.9 Hz), 2.63 (1H, dd, J=17.3, 5.7 Hz), 2.48 (1H, d, J=6.8 Hz)

[0674] (7) 350 mg (0.630 mmol) ofcis-4-hydroxy-1-(4-phenoxybenzyl)-5-trityloxymethylpyrrolidin-2-one wasdissolved in 14.0 ml of chloroform, treated with 439 μl (3.15 mmol) oftriethylamine and 244 μl (3.15 mmol) of methanesulfonyl chloride andstirred at room temperature for 1 hour. The reaction mixture wasconcentrated, treated with ethyl acetate, washed with water andsaturated brine, and then dried over anhydrous sodium sulfate. Afterconcentrating followed by column chromatography on silica gel elutingwith hexane:ethyl acetate (40:60-30:70) followed by concentrating intodryness, 400 mg (yield: 100%) ofcis-4-methanesulfonyloxy-1-(4-phenoxybenzyl)-5-trityloxymethylpyrrolidin-2-onewas obtained as a colorless oil.

[0675]¹H-NMR (300 MHz, CDCl₃)

[0676] δ: 7.41 (6H, m), 7.31 (11H, m), 7.12 (1H, m), 6.99 (2H, m), 6.88(4H, m), 5.29 (1H, m), 4.95 (1H, d, J=15.1 Hz), 3.69 (1H, m), 3.52 (1H,dd, J=10.6, 2.6 Hz), 3.39 (1H, dd, J=10.6, 4.1 Hz), 3.31 (1H, d, J=15.1Hz), 3.11 (1H, dd, J=16.6, 7.2 Hz), 2.92 (3H, s), 2.85 (1H, dd, J=16.6,7.9 Hz)

[0677] (8) 400 mg (0.630 mmol) ofcis-4-methanesulfonyloxy-1-(4-phenoxybenzyl)-5-trityloxymethylpyrrolidin-2-onewas dissolved in 2.00 ml of ether, treated with 4.00 ml of formic acid,and stirred at room temperature for 1 hour. After concentrating thereaction mixture followed by column chromatography on silica gel elutingwith hexane:ethyl acetate (10:90-0:100) followed by concentrating intodryness, 121 mg (yield: 49%) ofcis-5-hydroxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[0678]¹H-NMR. (300 MHz, CDCl₃)

[0679] δ: 7.35 (2H, m), 7.21 (2H, d, J=8.3 Hz), 7.12 (1H, m), 7.01 (2H,m), 6.96 (2H, d, J=8.7 Hz), 5.35 (1H, m), 4.90 (1H, d, J=15.1 Hz), 4.13(1H, d, J=15.1 Hz), 3.89 (2H, m), 3.77 (1H, m), 3.10 (3H, s), 2.84 (2H,m), 2.04 (1H, s)

[0680] (9) 121 mg (0309 mmol) ofcis-5-hydroxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-onewas dissolved in 5 ml of N,N-dimethylformamide, treated with 70.6 mg(0.618 mmol) of potassium thioacetate, stirred at 50° C. for 1.5 hours,treated further with 141 mg (1.24 mmol) of potassium thioacetate, andstirred at 70° C. for 3 hours. The reaction mixture was concentrated,treated with ethyl acetate, washed with water and saturated brine, andthen dried over anhydrous sodium sulfate. After concentrating followedby column chromatography on silica gel eluting with hexane:ethyl acetate(10:90) followed by concentrating into dryness, 17.1 mg (yield: 15%) oftrans-4-acetylthio-5-hydroxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[0681]¹H-NMR (300 MHz, CDCl₃)

[0682] δ: 7.34 (2H, m), 7.21 (2H, d, J=8.3 Hz), 7.11 (1H, m), 6.98 (4H,m), 4.90 (1H, d, J=15.3 Hz), 4.11 (1H, d, J=15.3 Hz), 4.03 (1H, m), 3.80(1H, dd, J=12.3, 3.2 Hz), 3.71 (1H, dd, J=12.3, 2.5 Hz), 3.38 (1H, m),3.10 (1H, dd, J=17.3, 9.0 Hz), 2.37 (1H, dd, J=17.3, 4.1 Hz), 2.30 (3H,s)

Example 21 (S)-4-Acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0683] (1) 700 mg (6.9 mmol, DAISO) of (R)-4-hydroxy-2-pyrrolidone and4.50 g (20.8 mmol) of 4-phenoxybenzyl chloride were dissolved in 6.0 mlof dimethylsulfoxide, treated with 1.20 g of powdered potassiumhydroxide with cooling on ice and then stirred at room temperature for14 hours. After adding ethyl acetate followed by washing 6 times withwater and then with saturated brine, the ethyl acetate layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure,and the residue was subjected to column chromatography on silica geleluting with ethyl acetate: methanol (100:0-99:1) to obtain 365 mg(yield: 19%) of (R)-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one as alight brown oil.

[0684]¹H-NMR (300 MHz, CDCl₃)

[0685] δ: 7.36-6.95 (9H, m), 4.51-4.48 (1H m), 4.45 (2H, s), 3.53 (1H,dd, J=10.8, 5.6 Hz), 3.21 (1H dd, J=10.8, 1.9 Hz), 2.75 (1H, dd, J=17.3,6.5 Hz), 2.44 (1H, dd, J=17.3, 2.2 Hz), 2.07 (1H brs).

[0686] (2) To a mixture of 300 mg (1.1 mmol) of(R)-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one, 207 μl (1.5 mmol) oftriethylamine and 1.5 ml of chloroform, a mixture of 115 μl (1.5 mmol)of methanesulfonyl chloride and 1.5 ml of chloroform was added dropwisewith cooling on ice, and the mixture was stirred for 30 minutes withcooling on ice. The reaction mixture was concentrated under reducedpressure and the residue obtained was treated with ethyl acetate andwashed 6 times with water followed by saturated brine, and then theethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain 372 mg (yield: 97%) of(R)-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-one as a brownoil.

[0687]¹H-NMR (300 MHz, CDCl₃)

[0688] δ: 7.37-6.96 (9H, m), 5.32-5.27 (1H, m), 4.50 (1H, d, J=14.7 Hz),4.44 (1H, d, J=14.7 Hz), 3.66 (1H, dd, J=11.9, 5.7 Hz), 3.52 (1H, dd,J=11.9, 2.0 Hz), 3.02 (3H, s), 2.87 (1H, dd, J=17.9, 6.8 Hz), 2.71 (1H,dd, J=17.9, 2.5 Hz).

[0689] (3) To a solution of 89 μl (1.2 mmol) of thioacetic acid in 1.0ml of methanol, 369 mg (1.1 mmol) of cesium carbonate was added at roomtemperature, and the mixture was concentrated under reduced pressure,and the residue was treated with 2.0 ml of N,N-dimethylformamide toobtain a solution of cesium thioacetate. This solution was added to amixture of 372 mg (1.0 mmol) of(R)-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-one obtainedabove and 3.0 ml of N,N-dimethylformamide, and the mixture was stirredat room temperature for 6 hours, and then treated with 15 μl (0.2 mmol)of thioacetic acid and 67 mg (0.2 mmol) of cesium carbonate. Afterstirring at room temperature for 15 hours followed by adding ethylacetate followed by washing 6 times with water and then with saturatedbrine, the ethyl acetate layer was dried over anhydrous sodium sulfate,concentrated under reduced pressure to obtain a residue which is thensubjected to column chromatography on silica gel eluding with ethylacetate:hexane (18:82) to obtain a crude product which was then purifiedby preparative thin layer silica gel chromatography (eluent: ethylacetate:hexane (1:1) solution) to obtain 80.3 mg (yield: 23%) of(S)-4-acethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as a colorlessoil.

[0690]¹H-NMR (300 MHz, CDCl₃)

[0691] δ: 7.36-6.94 (9H, m), 4.45 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 4.07-4.02 (1H, m), 3.74 (1H dd, J=10.6, 7.5 Hz), 3.16 (1H,dd, J=10.6, 4.9 Hz), 2.90 (1H dd, J=17.4, 8.9 Hz), 2.41 (1H, dd, J=17.4,6.0 Hz), 2.31 (3H, s).

Example 22 (S)-4-Mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0692] A mixture of 8 mg (0.02 mmol) of(S)-4-acethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained inExample 21, 0.1 ml of conc. hydrochloric acid and 0.1 ml of acetic acidwas stirred at 100° C. for 20 minutes. The reaction mixture was treatedwith ethyl acetate, washed 5 times with water and then with saturatedbrine, and the ethyl acetate layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain 6.9 mg (yield:99%) of (S)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[0693]¹H-NMR (300 MHz, CDCl₃)

[0694] δ: 7.37-6.95 (9H, m), 4.47 (1H, d, J=14.6 Hz), 4.40 (1H, d,J=14.7 Hz), 3.65 (1H, dd, J=10.0, 7.2 Hz)-3.60-3.48 (1H, m), 3.16 (1H,dd, J=10.0, 5.1 Hz), 2.91-(1H, dd, J=17.1, 8.1 Hz), 2.41 (1H, dd,J=17.1, 6.2 Hz), 1.87 (1H, d, J=6.7 Hz).

Example 23 (4S, 4′S)-4,4′-Dithiobis[1-(4-phenoxybenzyl)pyrrolidin-2-one]

[0695] A mixture of 4 mg (0.01 mmol) of(S)-4-acethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained inExample 21, 2 drops of conc. hydrochloric acid and 2 drops of aceticacid was stirred at 100° C. for 5 minutes. The reaction mixture wastreated with ethyl acetate, washed 2 times with water, 0.25 M potassiumiodide-iodine solution, a 5% aqueous solution of sodium sulfite and thenwith saturated brine, and the ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain 2 mg (yield: 30%) of (4S,4′S)-4,4′-dithiobis[1-(4-phenoxybenzyl)pyrrolidin-2-one] as a paleyellow powder.

[0696]¹H-NMR (300 MHz, CDCl₃)

[0697] δ:7.36-6.94 (18H, m), 4.47 (2H d, J=14.7 Hz), 4.38 (2H, d, J=14.7Hz), 3.61 (2H, dd, J=10.7, 6.9 Hz), 3.53-3.47 (2H, m), 3.27 (2H, dd,J=10.7, 3.5 Hz), 2.82 (2H, dd, J=17.5, 8.2 Hz), 2.49 (2H, dd, J=17.5,4.4 Hz).

Example 24 (R)-4-Acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0698] By a method similar to that in Example 21 and starting from(S)-4-hydroxy-2-pyrrolidone (DAISO),(R)-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one was obtained as apale yellow oil.

[0699] (S)-4-Hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one (yield: 21%)

[0700]¹H-NMR (300 MHz, CDCl₃)

[0701] δ: 7.37-6.94 (9H, m), 4.54-4.48 (1H, m), 4.48 (1H, d, J=14.6 Hz),4.42 (1H, d, J=14.6 Hz), 3.53 (1H, dd, J=10.8, 6.5 Hz), 3.21 (1H, dd,J=10.8, 2.1 Hz), 2.75 (1H, dd, J=17.3, 6.5 Hz), 2.44 (1H, d, J=17.3, 2.4Hz), 2.05 (1H, brs).

[0702] (S)-4-Methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-one(yield: 98%)

[0703]¹H-NMR (300 MHz, CDCl₃)

[0704] δ: 7.37-6.96 (9H, m), 5.32-5.27 (1H, m), 4.49 (1H, d, J=14.7 Hz),4.43 (1H, d, J=14.7 Hz), 3.66 (1H, dd, J=1.9, 5.7 Hz), 3.52 (1H, dd,J=11.9, 2.0 Hz), 3.02 (3H, s), 2.88 (1H, dd, J=17.9, 6.8 Hz), 2.71 (1H,dd, J=17.9, 2.5 Hz).

[0705] (R)-4-Acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one (yield: 44%)

[0706]¹H-NMR (300 MHz, CDCl₃)

[0707] δ: 7.37-6.95 (9H, m), 4.46 (1H, d, J=14.6 Hz), 4.40 (1H, d,J=14.6 Hz), 4.11-4.01 (1H, m), 3.75 (1H, dd, J=10.6, 7.5 Hz), 3.17 (1H,dd, J=10.6, 4.9 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.42 (1H, dd,J=17.4, 6.0 Hz), 2.32 (3H, s).

Example 25 (R)-4-Mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0708] By a method similar to that in Example 22 and starting from 10 mg(0.03 mmol) of (R)-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 24, 8.1 mg (yield: 92%) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[0709]¹H-NMR (300 MHz, CDCl₃)

[0710] δ: 7.37-6.95 (9H, m), 4.47 (1H, d, J=14.7 Hz), 4.40 (1H d, J=14.7Hz), 3.65 (1H, dd, J=10.0, 7.2 Hz), 3.60-3.48 (1H, m), 3.16 (1H, dd,J=10.0, 5.1 Hz), 2.91 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.0,6.2 Hz), 1.87 (1H d, J=6.7 Hz).

Example 26 (4R, 4′R)-4,4′-Dithiobis[1-(4-phenoxybenzyl)pyrrolidin-2-one]

[0711] By a method similar to that in Example 23 and starting from 10 mg(0.03 mmol) of (R)-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 24, 6.9 mg (yield: 79%) of (4R,4′R)-4,4′-dithiobis[1-(4-phenoxybenzyl)pyrrolidin-2-one] as a whitepowder.

[0712]¹H-NMR (300 MHz, CDCl₃)

[0713] δ: 7.36-6.94 (18H, m), 4.46 (2H, d, J=14.7 Hz), 4.42 (2H, d,J=14.7 Hz), 3.60 (2H, dd, J=10.7, 6.9 Hz), 3.52-3.45 (2H, m), 3.27 (2H,dd, J=10.7, 3.5 Hz), 2.81 (2H, dd, J=17.5, 8.2 Hz), 2.48 (2H, dd,J=17.5, 4.4 Hz).

Example 27 3-Acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0714] (1) A mixture of 3.20 g (16.2 mmol) of 4-phenoxybenzaldehyde,6.00 g (17.0 mmol) of β-alanine benzyl ester p-toluenesulfonate, 2.40 ml(17.1 mmol) of triethylamine and 150.0 ml of methanol was stirred atroom temperature for 22 hours, and then treated with 0.517 g (13.7 mmol)of sodium borohydride in portions. After stirring at room temperaturefor 10 minutes and concentrating under reduced pressure, the residueobtained was treated with ethyl acetate, washed 3 times with saturatedaqueous sodium hydrogen carbonate, once with water and then withsaturated brine, and the ethyl acetate layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain 5.70 g(yield: 98%) of an amine product as a colorless oil.

[0715]¹H-NMR (300 MHz, CDCl₃)

[0716] δ: 7.35-6.93 (14H, m), 5.13 (2H, s), 3.76 (2H, s), 2.92 (2H, t,J=6.3 Hz), 2.59 (2H, t, J=6.4 Hz)

[0717] (2) To a mixture of 5.70 g (15.9 mmol) of the amine product thusobtained, 4.50 g (16.7 mmol) of benzyl oxalate and 150 ml oftetrahydrofuran, 667 mg (16.7 mmol) of sodium hydride (60% in oil) whichhad previously been washed three times with hexane was added, and themixture was heated at 95° C. for 2 hours with stirring, cooled andconcentrated under reduced pressure to obtain a residue which was thentreated with ethyl acetate and washed three times with 6N hydrochloricacid and 6N hydrochloric acid-saturated brine, and the ethyl acetatelayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to obtain a residue which was then treated with ethylacetate, and the precipitate formed was collected by filtration toobtain 3.10 g (yield: 47%) of a benzyl ester product as a white powder.

[0718]¹H-NMR (300 MHz, CDCl₃)

[0719] δ: 8.80 (1H, brs), 7.38-6.94 (14K m), 5.26 (2H, s), 4.63 (2H, s),3.89 (2H, s).

[0720] (3) A mixture of 3.50 g (8.40 mmol) of the benzyl ester productthus-obtained, 0.80g of 10% palladium on activated charcoal, 100 ml ofethyl acetate and 100 ml of ethanol was stirred under hydrogenatmosphere at room temperature for 3 hours. After filtering insolublesoff and concentrating under reduced pressure, the residue obtained wastreated with ethyl acetate, washed twice with saturated aqueous sodiumhydrogen carbonate and saturated brine, and the ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrate under reducedpressure to obtain a residue which was then treated with ethyl acetate,and then the precipitate formed was collected by filtration to obtain1.70 g (yield: 72%) of 3-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one asa white powder.

[0721]¹H-NMR (300 MHz, DMSO-d₆)

[0722] δ: 7.41-6.96 (9H, m), 5.56 (1H, d, J=5.6 Hz), 4.37 (1H, d, J=15.2Hz), 4.31 (1H, d, J=15.2 Hz), 4.19-4.12 (1H, m), 3.22-3.06 (2H, m),2.31-2.21 (1H, m), 1.76-1.63 (1H, m).

[0723] (4) To a mixture of 50 mg of3-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one, 15 μl (0.2 mmol) ofmethanesulfonyl chloride and 1.0 ml of chloroform, 54 μl (0.2 mmol) oftriethylamine was added and the mixture was stirred at room temperaturefor 5 minutes and concentrated under reduced pressure, and the residueobtained was treated with ethyl acetate and washed three times withwater and then with saturated brine, and the ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure, and the residue obtained was purified by preparative thinlayer silica gel chromatography (eluent:ethyl acetate:hexane (33:67)) toobtain 52 mg (yield: 81%) of3-methanesulfonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as a colorlessoil.

[0724]¹H-NMR (300 MHz, CDCl₃)

[0725] δ 7.38-6.96 (9H m), 5.23 (1H, t, J=7.8 Hz), 4.47 (1H, d, J=14.6Hz), 4.41 (1H, d, J=14.5 Hz), 3.41-3.21 (2H, m), 3.31 (3H, s), 2.61-2.50(1H, m), 2.30-2.17 (1H, m).

[0726] (5) A mixture of 52 mg (0.1 mmol) of3-methanesulfonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one, 20 mg (0.2 mmol)of potassium thioacetate and 1.0 ml of N,N-dimethylformamide was stirredat room temperature for 12 hours and concentrated under reducedpressure, and the residue obtained was treated with ethyl acetate, andwashed three times with water and then with saturated brine, and theethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain 41 mg (yield: 84%) of3-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as a colorless oil.

[0727]¹H-NMR (300 MHz, CDCl₃)

[0728] δ: 7.37-6.95 (9H, m), 4.50 (1H, d, J=14.6 Hz), 4.41 (1H, d,J=14.6 Hz), 4.25 (1H, t, J=8.6 Hz), 3.35-3.23 (2H, m), 2.65-2.54 (1H,m), 2.39 (3H, s), 2.07-1.94 (1H, m).

Example 28 3-Benzoylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0729] To a solution of 64 μl (0.5 mmol) of thiobenzoic acid in 1.0 mlof methanol, 24 mg (0.2 mmol) of cesium carbonate was added and thesolvent was distilled off under reduced pressure to obtain cesiumthiobenzoate. This salt was added to a mixture of 163 mg (0.452 mmol) of3-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained inExample 27 and 2.0 ml of N,N-dimethylformamide, and the mixture wasstirred at room temperature for 3 days, and then 64 μl (0.5 mmol) ofthiobenzoic acid and 24 mg (0.2 mmol) of cesium carbonate were added.After stirring at room temperature further for 3 hours, 64 μl (0.5 mmol)of thiobenzoic acid and 24 mg (0.2 mmol) of cesium carbonate were added,and then ethyl acetate was added, and the mixture was washed twice withsaturated aqueous sodium hydrogen carbonate, water and then saturatedbrine, and the ethyl acetate layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain a residuewhich was then purified by preparative thin layer silica gelchromatography (eluent: ethyl acetate:hexane (1:1)) to obtain 133 mg(yield: 73%) of 3-benzoylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[0730]¹H-NMR (300 MHz, CDCl₃)

[0731] δ: 7.98-7.95 (2H, m), 7.59-6.97 (12H, m), 4.54 (1H, d, J=14.8Hz), 4.47 (1H, t, J=8.3 Hz), 4.46 (1H, d, J=14.8 Hz), 3.42-3.30 (2H, m),2.78-2.65 (1H, m), 2.17-2.05 (1H, m)

Example 29 3-Mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0732] A mixture of 41.2 mg (0.1 mmol) of3-acethylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example27, 0.5 ml of conc. hydrochloric acid and 0.5 ml of acetic acid wasstirred at 100° C. for 8 minutes, and cooled and concentrated underreduced pressure, and the residue obtained was treated with ethylacetate, washed 3 times with water and then with saturated brine, andthe ethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain 35.6 mg (yield: 98%) of3-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one as a colorless oil.

[0733]¹H-NMR (300 MHz, CDCl₃)

[0734] δ: 7.37-6.95 (9H, m), 4.48 (1H, d, J=14.6 Hz), 4.40 (1H, d,J=14.6 Hz), 3.72-3.66 (1H, m), 3.40-3.19 (2H, m), 2.52-2.39 (1H, m),2.32 (1H, d, J=4.3 Hz), 1.96-1.85 (1H, m).

Example 30 4-Acetylthio-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one

[0735] (1) 10.0 g (83.9 mmol) of 4-amino-3-hydroxybutyric acid wasdissolved in 400 ml of xylene, and treated with 124 ml (587 mmol) ofhexamethyldisilazane and 1 drop of trimethylsilyl chloride and thenheated under reflux for 16.5 hours. The reaction mixture wasconcentrated, and the residue was washed with diisopropyl ether toobtain 12.6 g (yield: 87%) of 4-trimethylsilyloxypyrrolidin-2-one as atan powder.

[0736]¹H-NMR (300 MHz, CDCl₃)

[0737] δ: 6.62 (1H, brs), 4.52 (1H, brs), 3.57 (1H, brd), 3.23 (1H,brd), 2.52(1H, m), 2.25 (1H, m), 0.11 (9H, brs)

[0738] (2) 5.0 g (40.3 mmol) of 4-fluorobenzaldehyde, 4.5 g (40.3 mmol)of 4-fluorophenol and 5.6 g (40.3 mmol) of potassium carbonate weredissolved in 100 ml of N,N-dimethylformamide, and stirred at 120° C. for14.5 hours. A cold water was added to the reaction mixture, which wasthen extracted twice with ethyl acetate, and the organic layer obtainedwas washed with water and saturated brine, and then dried over anhydroussodium sulfate. After concentrating under reduced pressure followed bycolumn chromatography on silica gel, the fraction eluted withhexane:ethyl acetate (97:3) was concentrated under reduced pressure andthe residue was washed with hexane to obtain 7.7 g (yield: 88%) of4-(4′-fluorophenoxy)benzaldehyde as a white powder.

[0739]¹H-NMR (300 MHz, CDCl₃)

[0740] δ: 9.93 (1H, s), 7.85 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=7.9 Hz),7.05 (2H, d, J=7.9 Hz), 7.03 (2H, d, J=8.8 Hz)

[0741] (3) 2.0 g (9.3 mmol) of 4-(4′-fluorophenoxy)benzaldehyde wasdissolved in 40 ml of methanol, treated slowly with 422 mg (11.2 mmol)of sodium borohydride and then stirred at room temperature for 2 hours.The reaction mixture was made acidic with a dilute hydrochloric acid,concentrated under reduced pressure and extracted twice with ethylacetate, and the organic layer obtained was washed with water andsaturated brine, and then dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was washed with hexaneto obtain 1.7 g (yield: 85%) of 4-(4′-fluorophenoxy)benzylalcohol as awhite powder.

[0742]¹H-NMR (300 MHz, CDCl₃)

[0743] δ: 7.33 (2 H, d, J=8.7 Hz), 7.01 (2H, d, J=10.3 Hz), 6.99 (2H, d,J=8.7 Hz), 6.96 (2H, d, J=10.3 Hz), 4.67 (2H, d, J=5.6 Hz), 1.64 (1H, t,J=5.6 Hz)

[0744] (4) 1.7 g (7.9 mmol) of 4-(4′-fluorophenoxy)benzylalcohol wasdissolved in chloroform and stirred on an ice bath. 639 μl (7.9 mmol) ofpyridine and 632 μl (8.7 mmol) of thionyl chloride were added slowly,and the mixture was stirred on an ice bath for 0.5 hours and then atroom temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure, treated with water and extracted twice withethyl acetate, and then the organic layer obtained was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating under reducer pressure, 1.7 g (yield: 91%) of4-(4′-fluorophenoxy)benzyl chloride was obtained as a colorless oil.

[0745]¹H-NMR (300 MHz, CDCl₃)

[0746] δ: 7.33 (2H, d, J=8.6 Hz), 7.01 (2H, d, J=7.6 Hz), 6.99 (2H, d,J=7.6 Hz), 6.93 (2H, d, J=8.6 Hz), 4.56 (2H, s)

[0747] (5) 1.25 g (7.2 mmol) of 4-trimethylsilyloxypyrrolidin-2-one and1.70 g (7.2 mmol) of 4-(4′-fluorophenoxy)benzyl chloride were dissolvedin 20.0 ml of dimethyl sulfoxide, and 475 mg (7.2 mmol) of pulverizedpotassium hydroxide and a catalytic amount of potassium iodide wereadded, and the mixture was stirred at room temperature for 5.5 hours.The reaction mixture was treated with water and extracted twice withethyl acetate, and the organic layer obtained was washed 4 times withwater and then with saturated brine, and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure followed by columnchromatography on silica gel eluting with chloroform:methanol (92:8),914 mg (yield: 42%) of4-hydroxy-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one was obtained asa tan powder.

[0748]¹H-NMR (300 MHz, CDCl₃)

[0749] δ: 7.20 (2H, d, J=8.6 Hz), 7.01 (2H, d, J=10.6 Hz), 6.99 (2H, d,J=10.6 Hz), 6.92 (2H, d, J=8.6 Hz), 4.91 (1H, m), 4.49 (1H, d, J=14.9Hz), 4.41 (1H, d, J=14.8 Hz), 3.53 (1H, dd, J=10.8, 5.6 Hz), 3.21 (1H,dd, J=10.8, 2.0 Hz); 2.75 (1H, dd, J=17.4, 6.6 Hz), 2.44 (1H, dd,J=17.4, 2.4 Hz), 2.10 (1H, d, J=4.3 Hz)

[0750] (6) 914 mg (3.0 mmol) of4-hydroxy-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one was dissolvedin 20 ml of pyridine, treated with 464 μl (6.0 mmol) of methanesulfonylchloride and stirred at 50° C. for 1 hour. The reaction mixture wastreated with water and extracted twice with ethyl acetate, and theorganic layer obtained was washed twice with water and then withsaturated brine, and then the ethyl acetate layer was dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was precipitated from hexane-ethyl acetate to obtain 926 mg(yield: 81%) of4-methanesulfonyloxy-1-(4-′4′-fluorophenoxy)benzyl)pyrrolidin-2-one as agrayish tan powder.

[0751]¹H-NMR (300 MHz, CDCl₃)

[0752] δ: 7.19 (2H, d, J=8.5 Hz), 7.02 (2H, d, J=10.7 Hz), 7.00 (2H, d,J=10.7 Hz), 6.93 (2H, d, J=8.5 Hz), 5.29 (1H, m), 4.49 (1H, d, J=14.9Hz), 4.43 (1H, d, J=14.8 Hz), 3.66 (1H, dd, J=11.9, 5.7 Hz), 3.52 (1H,dd, J=11.9, 2.0 Hz), 3.03 (3H, s), 2.75 (1H, dd, J=17.9, 6.8 Hz), 2.71(1H, dd,]=17.9, 2.6 Hz)

[0753] (7) 925 mg (2.4 mmol) of4-methanesulfonyloxy-1-(4-′4′-fluorophenoxy)benzyl)pyrrolidin-2-one wasdissolved in 30 ml of ethanol, treated with 822 mg (7.2 mmol) ofpotassium thioacetate and heated under reflux for 1 hour. The reactionmixture was concentrated under reduced pressure, treated with water andextracted twice with ethyl acetate, and the organic layer obtained waswashed with water and saturated brine, and then dried over anhydroussodium sulfate. After concentrating under reduced pressure, the residuewas subjected to column chromatography on silica gel eluting withhexane:ethyl acetate (70:30) to obtain 834 mg (yield: 97%) of4-acetylthio-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one as a paleyellow oil.

[0754]¹H-NMR (300 MHz, CDCl₃)

[0755] δ: 7.18 (2H, d, J=8.6 Hz), 7.02 (2H, d, J=9.7 Hz), 7.00 (2H, d,J=9.7 Hz), 6.92 (2H, d, J=8.6 Hz), 4.45 (1H, d, J=15.1 Hz), 4.40 (1H, d,J=15.1 Hz), 4.05 (1H, m), 3.75 (1H, dd, J=10.6, 7.6 Hz), 3.17 (1H, dd,J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.42 (1H, dd, J=17.4,6.1 Hz), 2.32 (3H, s)

Example 31 4-Mercapto-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one

[0756] 250 mg (0.7 mmol) of4-acetylthio-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one obtained inExample 30 was dissolved in a mixture of 4 m of acetic acid and 1 ml ofconc. hydrochloric acid, and stirred at 100° C. for 3 hours. Thereaction mixture was concentrated under reduced pressure, treated withethyl acetate and washed twice with water and then with saturated brine,and the organic layer was dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was subjected tocolumn chromatography on silica gel eluting with hexane:ethyl acetate(70:30-50:50) to obtain 163 mg (yield: 73%) of4-mercapto-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one as a colorlessoil.

[0757]¹H-NMR (300 MHz, CDCl₃)

[0758] δ: 7.21 (2H, d, J=8.6 Hz), 7.02 (2H d, J=10.2 Hz), 7.00 (2H, d,J=10.2 Hz), 6.93 (2H d, J=8.6 Hz), 4.47 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 3.65 (1H, dd, J=10.0, 7.2 Hz), 3.54 (1H, m), 3.16 (1H, dd,J=10.0, 5.0 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1,6.1 Hz), 1.86 (1H, d, J=6.7 Hz)

Example 32 4-Acetylthio-1-(4-(4′-chlorophenoxy)benzyl)pyrrolidin-2-one

[0759] By a method similar to that in Example 30 and starting from 1.72g (6.8 mmol) of 4-(4′-chlorophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 4-chlorophenol and 1.20 g (6.8 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 702 mg (yield: 27%) of4-acetylthio-1-(4-(4′-chlorophenoxy)benzyl)pyrrolidin-2-one was obtainedas a pale tan powder.

[0760]¹H-NMR (300 MHz, CDCl₃)

[0761] δ 7.30 (2H, d, J=8.9 Hz), 7.20 (2H, d, J=8.5 Hz), 6.96 (2H, d,J=8.5 Hz), 6.94 (2H, d, J=8.9 Hz), 4.46 (1H, d, J=15.2 Hz), 4.41 (1H, d,J=15.2 Hz), 4.06 (1H, m), 3.76 (1H, dd, J=10.6, 7.5 Hz), 3.18 (1H, dd,J=10.6, 5.0 Hz), 2.92 (1H, dd, J=17.4, 9.0 Hz), 2.43 (1H, dd, J=17.4,6.1 Hz), 2.32 (3H, s)

Example 33 4-Mercaoto-1-(4-(4′-chlorophenoxy)benzyl)pyrrolidin-2-one

[0762] By a method similar to that in Example 31 and starting from 253mg (0.7 mmol) of4-acetylthio-1-(4-(4′-chlorophenoxy)benzyl)pyrrolidin-2-one obtained inExample 32, 209 mg (yield: 93%) of4-mercaoto-1-(4-(4′-chlorophenoxy)benzyl)pyrrolidin-2-one was obtainedas a colorless oil.

[0763]¹H-NMR (300 MHz, CDCl₃)

[0764] δ: 7.29 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.5 Hz), 6.96 (2H, d,J=8.5 Hz), 6.94 (2H, d, J=8.8 Hz), 4.48 (1H, d, J=14.7 Hz), 4.40 (1H, d,J=14.7 Hz), 3.66 (1H, dd, J=10.0, 7.2 Hz), 3.55 (1H, m), 3.17 (1H, dd,J=10.0, 5.0 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1,6.1 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 34 4-Acetylthio-1-(4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one

[0765] By a method similar to that in Example 30 and starting from 1.92g (6.5 mmol) of 4-(4′-bromophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 4-bromophenol and 1.10 g (6.5 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 955 mg (yield: 35%) of4-acetylthio-1-(4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one was obtainedas a pale tan powder.

[0766]¹H-NMR (300 MHz, CDCl₃)

[0767] δ: 7.44 (2H, d, J=8.9 Hz), 7.20 (2H, d, J=8.5 Hz), 6.96 (2H, d,J=8.5 Hz), 6.89 (2H, d, J=8.9 Hz), 4.46 (1H, d, J=14.9 Hz), 4.41 (1H, d,J=14.9 Hz), 4.06 (1H, m), 3.76 (1H, dd, J=10.6, 7.5 Hz), 3.18 (1H, dd,J=10.6, 5.0 Hz), 2.92 (1H, dd, J=17.4, 9.0 Hz), 2.43 (1H, dd, J=17.4,6.1 Hz), 2.32 (3H, s)

Example 35 4-Mercapto-1-(4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one

[0768] By a method similar to that in Example 31 and starting from 330mg (0.8 mmol) of4-acetylthio-1-(4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one obtained inExample 34, 240 mg (yield: 79%) of4-mercaoto-1-(4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one was obtained asa colorless oil.

[0769]¹H-NMR (300 MHz, CDCl₃)

[0770] δ: 7.44 (2H, d, J=8.9 Hz), 7.23 (2H, d, J=8.6 Hz), 6.96 (2H, d,J=8.6 Hz), 6.88 (2H, d, J=8.9 Hz), 4.48 (1H, d, J=14.8 Hz), 4.40 (1H, d,J=14.8 Hz), 3.66 (1H, dd, J=10.0, 7.2 Hz), 3.55 (1H, m), 3.17 (1H, dd,J=10.0, 5.0 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.43 (1H, dd, J=17.1,6.1 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 36 4-Acetylthio-1-(4-(4′-methoxyphenoxy)benzyl)pyrrolidin-2-one

[0771] By a method similar to that in Example 30 and starting from 1.75g (7.0 mmol) of 4-(4′-methoxyphenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 4-methoxyphenol and 1.21 g (7.0 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 866 mg (yield: 33%) of4-acetylthio-1-(4-(4′-methoxyphenoxy)benzyl)pyrrolidin-2-one wasobtained as a pale tan powder.

[0772]¹HMR (300 MHz, CDCl₃)

[0773] δ: 7.15 (2H, d, J=8.4 Hz), 6.98 (2H, d, J=9.0 Hz), 6.89 (2H, d,J=8.4 Hz), 6.89 (2H, d, J=9.0 Hz), 4.45 (1H, d, J=15.1 Hz), 4.38 (1H, d,J=15.1 Hz), 4.05 (1H, m), 3.81 (3H, s), 3.74 (1H, dd, J=10.6, 7.6 Hz),3.16 (1H, dd, J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.41 (1H,dd, J=17.4, 6.0 Hz), 2.31 (3H, s)

Example 37 4-Mercapto-1-(4-(4′-methoxyphenoxy)benzyl)pyrrolidin-2-one

[0774] By a method similar to that in Example 31 and starting from 291mg (0.9 mmol) of4-acetylthio-1-(4-(4′-methoxyphenoxy)benzyl)pyrrolidin-2-one obtained inExample 36, 291 mg (yield: 98%) of4-mercaoto-1-(4-(4′-methoxyphenoxy)benzyl)pyrrolidin-2-one was obtainedas a colorless oil.

[0775]¹H—NMR (300 MHz, CDCl₃)

[0776] δ: 7.17 (2H, J=8.4 Hz), 6.98 (2H, d, J=9.0 Hz), 6.90 (2H, d,J=8.4 Hz), 6.89 (2H, d, J=9.0 Hz), 4.45 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 3.81 (3H s), 3.64 (1H, dd, J=10.0, 7.3 Hz), 3.53 (1H, m),3.15 (1H dd, J=10.0, 5.1 Hz), 2.91 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H,dd, J=17.1, 6.2 Hz), 1.86 (1H, d, J=6.8 Hz)

Example 38Trans-4-acetylthio-5-benzyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0777] (1) 14.3 g (28.3 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-O-benzyl-D,L-serine methyl estersynthesized in Example 20 was dissolved in 140 ml of ethanol, treatedwith 11.1 ml (28.3 mmol) of a 20% solution of sodium ethoxide in ethanoland stirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, treated with 10% aqueous citricacid and extracted twice with ethyl acetate and the organic layer waswashed twice with water and then with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reducer pressureinto dryness, the residue was dissolved in 220 ml of acetonitrile,treated with 700 ml of water and heated under reflux for 1 hour. Thereaction mixture was concentrated under reduced pressure, dissolved in165 ml of methanol, treated with 987 mg (26.1 mmol) of sodiumborohydride in portions with stirring, and then stirred at roomtemperature further for 1 hour. The reaction mixture was concentratedunder reduced pressure, treated with water and then extracted threetimes with ethyl acetate. The organic layer was washed twice with waterand then with saturated brine, and dried over anhydrous sodium sulfate.After concentrating under reduced pressure, the residue was subjected tocolumn chromatography on silica gel eluting with hexane:ethyl acetate(20:80-0:100) to obtain 8.32 g (yield: 73%) ofcis-5-benzyloxymethyl-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[0778]¹H-NMR (300 MHz, CDCl₃)

[0779] δ: 7.34 (7H, m), 7.12 (3H, m), 6.98 (2H, m), 6.92 (2H d, J=8.3Hz), 4.80 (1H, d, J=15.3 Hz), 4.53 (1H, m), 4.48 (1H, d, J=11.9 Hz),4.40 (1H, d, J=11.9 Hz), 4.00 (1H, d, J=15.3 Hz), 3.71 (1H, m), 3.65(2H, m), 2.74 (1H, dd, J=17.0, 7.9 Hz), 2.53 (1H, dd, J=17.0, 6.0 Hz)

[0780] (2) 500 mg (1.24 mmol) ofcis-5-benzyloxymethyl-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidin-2-one wasdissolved in 20 ml of chloroform, treated with 864 μl (6.20 mmol) oftriethylamine and 480 μl (6.20 mmol) of methanesulfonyl chloride withcooling on ice and then stirred at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure, treated withethyl acetate, washed with water and saturated brine, and then driedover anhydrous sodium sulfate. After concentrating under reducedpressure followed by column chromatography on silica gel eluting withhexane:ethyl acetate (30:70-20:80), 560 mg (yield: 94%) ofcis-5-benzyloxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[0781]¹H-NMR (300 MHz, CDCl₃)

[0782] δ: 7.34 (7H, m), 7.13 (31 m), 7.00 (2H, m), 6.92 (2H, d, J=8.7Hz), 5.27 (1H, m), 4.85 (1H, d, J=15.1 Hz), 4.47 (1H, d, J=11.9 Hz),4.42 (1H, d, J=11.9 Hz), 4.06 (1H, d, J=15.1 Hz), 3.82 (1H, m), 3.66(2H, m), 2.98 (3H, s), 2.91 (1H, dd, J=17.0, 6.6 Hz), 2.76 (1H, dd,J=17.0, 7.9 Hz)

[0783] (5) 560 mg (1.16 mmol) of5-benzyloxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-onewas dissolved in 20 ml of ethanol, treated with 265 mg (2.32 mmol) ofpotassium thioacetate, heated under reflux for 4 hours, treated furtherwith 265 mg (2.32 mmol) of potassium thioacetate, and then heated underreflux for 2 hours. The reaction mixture was concentrated under reducedpressure, treated with ethyl acetate, washed with water and saturatedbrine, and then dried over anhydrous sodium sulfate. After concentratingunder reduced pressure followed by column chromatography on silica geleluting with hexane:ethyl acetate (60:40-50:50), 245 mg (yield: 46%) oftrans-4-acetylthio-5-benzyloxymehyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[0784]¹H-NMR (300 MHz, CDCl₃)

[0785] δ: 7.32 (7H, m), 7.14 (2H, d, J=8.7 Hz), 7.10 (1H, m), 6.98 (2H,m), 6.92 (2H, d, J=8.7 Hz), 4.88 (1H, d, J=15.3 Hz), 4.49 (1H, d, J=12.1Hz), 4.39 (1H, d, J=12.1 Hz), 3.99 (1H, d, J=15.3 Hz), 3.99 (1H, m),3.57 (2H, m), 3.45 (1H, m), 3.13 (1H, dd, J=17.8, 9.1 Hz), 2.33 (1H, m),2.29 (3H, s)

Example 39Trans-5-benzyloxymethyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[0786] 145 mg (0.314 mmol) oftrans-4-acetylthio-5-benzyloxymehyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 38 was dissolved in a mixture of 1 ml of acetic acidand 1 ml of conc. hydrochloric acid, and stirred at 100° C. for 20minutes. The reaction mixture was poured into an iced water andextracted twice with ethyl acetate, and the organic layer obtained waswashed twice with water and then with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressurefollowed by column chromatography on silica gel eluting withhexane:ethyl acetate (50:50), 34.2 mg (yield: 26%) oftrans-5-benzyloxymethyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-onewas obtained as a colorless oil.

[0787]¹H-NMR (300 MHz, CDCl₃)

[0788] δ: 7.33 (7H, m), 7.15 (2H, d, J=8.7 Hz), 7.10 (1H, m), 6.98 (2H,m), 6.92 (2H, d, J=8.7 Hz), 4.91 (1H, d, J=15.1 Hz), 4.46 (1H, d, J=11.9Hz), 4.42 (1H, d, J=11.9 Hz), 3.97 (1H d, J=15.1 Hz), 3.50 (2H, m), 3.42(2H, m)., 3.05 (1H, dd, J=17.3, 7.9 Hz), 2.36 (1H, dd, J=17.3, 4.9 Hz),1.79 (1H, d, J=6.8 Hz).

Example 40 4-Acetylthio-1-(3-phenoxybenzyl)pyrrolidin-2-one

[0789] By a method similar to that in Example 30 and starting from 1.23g (5.6 mmol) of 3-phenoxybenzyl chloride prepared from3-phenoxybenzaldehydr (TOKYO KASEI) and 0.97 g (5.6 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 704 mg (yield: 37%) of4-acetylthio-1-(3-phenoxybenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[0790]¹H-NMR (300 MHz, CDCl₃)

[0791] δ: 7.38-7.28 (3H, m), 7.12 (1H, t, J=7.4 Hz), 7.02-6.86 (5H, m),4.48 (1H, d, J=14.9 Hz), 4.39 (1H, d, J=14.9 Hz), 4.05 (1H, m), 3.75(1H, dd, J=10.6, 7.5 Hz), 3.17 (1H, dd, J=10.6, 4.9 Hz), 2.91 (1H, dd,J=17.4, 8.9 Hz), 2.41 (1H, dd, J=17.4, 5.9 Hz), 2.31 (3H, s)

Example 41 4-Mercapto-1-(3-phenoxybenzyl)pyrrolidin-2-one

[0792] By a method similar to that in Example 31 and starting from 200mg (0.59 mmol) of 4-acetylthio-1-(3-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 40, 104 mg (yield 59%) of4-mercapto-1-(3-phenoxybenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[0793]¹H-NMR (300 MHz, CDCl₃)

[0794] δ: 7.38-7.26 (3H, m), 7.12 (1H, t, J=7.4 Hz), 7.03-6.87 (5H, m),4.48 (1H, d, J=14.9 Hz), 4.40 (1 H, d, J=14.9 Hz), 3.65 (1H, dd, J=10.1,7.2 Hz), 3.53 (1H, m), 3.16 (1H dd, J=10.1, 5.0 Hz), 2.91 (1H, dd,J=17.1, 8.1 Hz), 2.41 (1H, dd, J=17.1, 6.1 Hz), 1.84 (1H, d, J=6.8 Hz).

Example 42 and Example 433-Acetylthio-1-(4-phenoxybenzyl)piperidine-2,6-dione and3-acetylthio-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione

[0795] (1) A mixture of 4.91 g (14.9 mmol) of ethyl α-phenylN-t-butyloxycarbonylglutamate prepared by the method known in literature(Tetrahedron Asymmetry, Vol. 6, No.6, pp1249-1252, 1995), 4.28 g (22.3mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,15.8 ml (113.1 mmol) of triethylamine, 3.56 (17.9 mmol) of4-phenoxybenzylamine and 77 ml of chloroform was stirred at 55° C. for30 minutes, treated with 2.41 g (17.9 mmol) of 1-hydroxybenzotriazoleand stirred at 55° C. for two days. The reaction mixture wasconcentrated under reduced pressure, and the residue was treated withethyl acetate, washed three times with saturated aqueous sodium hydrogencarbonate, once with saturated brine, three times with a 10% aqueoussolution of citric acid and then once with saturated brine. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure, and the residue was subjected to columnchromatography on silica gel eluting with hexane:ethyl acetate (25:75)to obtain 1.46 g (yield: 24%) of3-(t-butyloxycarbonylamino)-1-(4-phenoxybenzyl)piperidine-2,6-dione as abrown oil.

[0796]¹H-NMR (300 MHz, CDCl₃)

[0797] δ: 7.35-6.89 (9H, m), 5.40 (1H, brs), 4.93 (1H, d, J=13.8 Hz),4.88 (1H, d, J=13.8 Hz), 4.31-4.26 (1H, m), 2.93-2.85 (1H, m), 2.78-2.66(1H, m), 2.51-2.47 (1H, m), 1.88-1.73 (1H, m), 1.46 (9H, s).

[0798] (2) Immediately after dissolving 1.21 g (3.0 mmol) of3-(t-butyloxycarbonylamino)-1-(4-phenoxybenzyl)piperidine-2,6-dione in15 ml of trifluoroacetic acid, the solution was concentrated underreduced pressure to obtain a residue which was then treated with ethylacetate and washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated brine, and the ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to obtain a residue which was then treated with ethyl acetate,and the precipitate formed was collected by filtration, wherebyobtaining 823 mg (yield: 90%) of3-amino-1-(4-phenoxybenzyl)piperidine-2,6-dione as a pale blue powder.

[0799]¹H-NMR (300 MHz, CDCl₃)

[0800] δ: 7.36-6.89 (9H, m), 4.91 (2H, s), 3.53 (1H, dd, J=12.4, 5.1Hz), 2.94-2.85 (1H, m), 2.74-2.61 (1H, m), 2.27-2.18 (1R, m), 1.87-1.72(1H, m).

[0801] (3) 800 mg (2.6 mmol) of3-amino-1-(4-phenoxybenzyl)piperidine-2,6-dione was suspended in 2 ml ofethyl acetate, and then immediately after adding 2 ml of a 25% solutionof hydrogen bromide in acetic acid the mixture was concentrated underreduced pressure to obtain a residue to which then ethyl acetate wasadded, and the precipitate formed was collected by filtration to give881 mg of 3-amino-1-(4-phenoxybenzyl)piperidine-2,6-dione hydrobromide.A mixture of 1.20 g (3.1 mmol) of3-amino-1-(4-phenoxybenzyl)piperidine-2,6-dione hydrobromide thusobtained, 7 ml (61.4 mmol) of 8.84 N aqueous hydrogen bromide, 7 ml ofacetonitrile and 7 ml of water was cooled to −5° C., and treateddropwise over 1 hour with an aqueous solution prepared by mixing 1.83 g(15.4 mmol) of potassium bromide and 530 mg (7.7 mmol) of sodium nitritewith 10 ml of water. Thereafter, 21 ml of acetonitrile and 14 ml ofwater were added, and the mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure, andthe residue was treated with ethyl acetate, washed twice with water andthen with saturated brine. The ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthe residue was subjected to column chromatography on silica gel elutingwith ethyl acetate:hexane (10:90) to obtain 424 mg of a mixture (ofabout 2:1) of 3-bromo-1-(4-phenoxybenzyl)piperidine-2,6-dione and3-bromo-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione as a palepurple oil.

[0802]¹H-NMR (300 MHz, CDCl₃)

[0803] δ: 7.43-7.40 (0.7H, m), 7.12-7.07 (0.7H, m), 7.35-6.85 (7.3H, m),4.97 (1H, d, J=13.8 Hz), 4.88 (1H, d, J=13.8 Hz), 4.72 (1H, t, J=3.1Hz), 3.12-3.00 (14 m), 2.81-2.73 (1H, m), 2.44-2.20 (2H, m).

[0804] (4) A mixture consisting of 200 mg of the mixture (of about 2:1)of 3-bromo-1-(4-phenoxybenzyl)piperidine-2,6-dione and3-bromo-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione, 67 mg (0.6mmol) of potassium thioacetate and 2 ml of N,N-dimethylformamide wasstirred at room temperature for 30 minutes and concentrated underreduced pressure, and the residue obtained was treated with ethylacetate and washed three times with water and then with saturated brine,and the ethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the residue obtained wassubjected to high pressure liquid chromatography (eluent: 65%acetonitrile/0.01 N phosphate buffer (pH6.3)) to obtain 108 mg of3-acetylthio-1-(4-phenoxybenzyl)piperidine-2,6-dione as a pale blue oiland 63 mg of3-acetylthio-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione as a palered oil. 3-Acetylthio-1-(4-phenoxybenzyl)piperidine-2,6-dione (Example42)

[0805]¹H-NMR (300 MHz, CDCl₃)

[0806] δ:7.35-6.90 (1H, m), 4.96 (1H, d, J=13.7 Hz), 4.88 (1H, d, J=13.8Hz), 4.45 (1H, dd, J=9.7, 4.9 Hz), 2.91-2.70 (2H, m), 2.42 (3H, s),2.32-2.26 (1H, m), 2.14-2.04 (1H, m).

[0807] 3-Acetylthio-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione(Example 43)

[0808]¹H-NMR (300 MHz, CDCl₃)

[0809] δ: 7.42-7.27 (4H, m), 6.91-6.85 (4H, m), 4.95 (1H, d, J=13.8 Hz),4.88 (1H, d, J=13.8 Hz), 4.44 (1H, dd, J=9.8, 4.9 Hz), 2.90-2.70 (2H,n), 2.41 (3H, s), 2.34-2.23 (1H, m), 2.14-2.01 (1H, m).

Example 44 3-Benzoylthio-1-(4-phenoxybenzyl)piperidine-2,6-dione

[0810] 100 mg of a mixture (of about 5:1) of3-bromo-1-(4-phenoxybenzyl)piperidine-2,6-dione and3-bromo-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione obtainedsimilarly to Example 42 was processed similarly to 28 to obtain 86 mg of3-benzoylthio-1-(4-phenoxybenzyl)piperidine-2,6-dione as a pale yellowoil.

[0811]¹H-NMR (300 MHz, CDCl₃)

[0812] δ: 8.00-7.95 (2H, m), 7.65-6.86 (12H, m), 5.00 (1H, d, J=13.7Hz), 4.93 (1H, d, J=13.7 Hz), 4.67 (1H, dd, J=9.7, 4.9), 2.98-2.76 (2H,m), 2.44-2.13 (2H, m).

Example 45 Mixture of 3-mercapto-1-(4-phenoxybenzyl)piperidine-2,6-dioneand 1-[4-(4-bromophenoxy)benzyl]-3-mercaptopiperidine-2,6-dione

[0813] A mixture consisting of 150 mg of a mixture (of about 2:1) of3-bromo-1-(4-phenoxybenzyl)piperidine-2,6-dione and3-bromo-1-[4-(4-bromophenoxy)benzyl]piperidine-2,6-dione obtainedsimilarly to Example 42, 50 mg (0.04 mmol) of potassium thioacetate and2 ml of N,N-dimethylformamide was stirred at room temperature for 45minutes and concentrated under reduced pressure, and the residueobtained was treated with ethyl acetate and washed twice with water andthen with saturated brine. The ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthe residue obtained was dissolved in a mixture of 1 ml of acetic acidand 1 ml of conc. hydrochloric acid, and stirred at 100° C. for 25minutes. After concentrating under reduced pressure, the residueobtained was treated with ethyl acetate, washed three times with water,saturated aqueous sodium hydrogen carbonate, phosphate buffer (pH6.8)and then saturated brine, and the ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain a residue, which was then purified by preparative thin layersilica gel chromatography (eluent: ethyl acetate:hexane (2:1)) to obtaina mixture (of about 2:1) of3-mercapto-1-(4-phenoxybenzyl)piperidine-2,6-dione and1-[4-(4-bromophenoxy)benzyl]-3-mercaptopiperidine-2,6-dione.

[0814]¹H-NMR (300 MHz, CDCl₃)

[0815] δ: 7.43-7.40 (0.7H, m), 7.15-7.07 (0.7H, m), 7.35-6.85 (7.3H, m),4.96 (1H, d, J=13.8 Hz), 4.89 (1H d, J=13.8 Hz), 3.97-3.93 (1H, m),2.99-2.88 (1H, m), 2.75-2.65 (1H, m), 2.40 (1H, d, J=4.6 Hz), 2.39-2.27(1H, m), 2.09-1.96 (1H, m).

Example 46 3-Acetylthio-1-(4-phenoxybenzyl)piperidin-2-one

[0816] (1) To a mixture of 700 mg of 3-hydroxy-2-piperidone (6.1 mmol,Aldrich), 512 mg (9.1 mmol) of pulverized potassium hydroxide and 6 mlof dimethylsulfoxide, 1.33 g (6.1 mmol) of phenoxybenzyl chloride wasadded with cooling on ice, and the mixture was stirred at roomtemperature for 16 hours. After adding ethyl acetate, the mixture waswashed with 1N hydrochloric acid, 6 times with water and then withsaturated brine. The ethyl acetate layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure, and the residue wassubjected to column chromatography on silica gel eluting with ethylacetate: n-hexane (20:80) to obtain 781 mg (yield: 43%) of3-hydroxy-1-(4-phenoxybenzyl)piperidin-2-one as a pale yellow oil.

[0817]¹H-NMR (300 MHz, CDCl₃)

[0818] δ: 7.35-6.95 (9H, m), 4.60 (1H, d, J=14.5 Hz), 4.49 (1H, d,J=14.5 Hz), 4.13-4.06 (1H, m), 3.26-3.22 (2H, n), 2.30-2.26 (1H, n),1.93-1.69 (4H, m).

[0819] (2) 909 mg (3.1 mmol) of3-hydroxy-1-(4-phenoxybenzyl)piperidin-2-one was processed similarly toExample 21 to obtain 1.13 g (yield: 99%) of3-methanesulfonyloxy-1-(4-phenoxybenzyl)piperidin-2-one as a pale yellowoil.

[0820]¹H-NMR (300 MHz, CDCl₃)

[0821] δ: 7.37-6.96 (9H, m), 5.06 (1H, dd, J=7.9, 5.7 Hz), 4.58 (1H, d,J=14.6 Hz), 4.52 (1H, d, J=14.4 Hz), 3.31 (3H, s), 3.29-3.20 (2H, m),2.27-1.81 (4H, n).

[0822] (3) A mixture of 400 mg (1.1 mmol) of3-methanesulfonyloxy-1-(4-phenoxybenzyl)piperidin-2-one, 146 mg (1.3mmol) of potassium thioacetate and 4 ml of N,N-dimethylformamide wasstirred at room temperature for 1 hour and then concentrated underreduced pressure, and the residue obtained was treated with ethylacetate, washed twice with water, twice with a saturated aqueoussolution of sodium hydrogen carbonate and then with saturated brine. Theethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and the residue obtained wassubjected to column chromatography on silica gel eluting with ethylacetate:hexane (20:80) to obtain 328 mg (yield: 87%) of3-acetylthio-1-(4-phenoxybenzyl)piperidin-2-one as a pale red to palebrown oil.

[0823]¹H-NMR (300 MHz, CDCl₃)

[0824] δ: 7.36-6.94 (9H, m), 4.60 (1H, d, J=14.5 Hz), 4.54 (1H, d,J=14.4 Hz), 4.29 (1H, dd, J=7.7, 5.5 Hz), 3.34-3.21 (2H, m), 2.38 (3H,s), 2.30-2.20 (1H, m), 2.00-1.81 (3H, m).

Example 47 3-Benzoylthio-1-(4-phenoxybenzyl)piperidin-2-one

[0825] A mixture of 200 mg (0.5 mmol) of3-methanesulfonyloxy-1-(4-phenoxybenzyl)piperidin-2-one obtained inExample 46, 751 μl (0.6 mmol) of thiobenzoic acid, 87 mg (0.3 ml) ofcesium carbonate and 1 ml of N,N-dimethylformamide was stirred at roomtemperature for 15 hours, treated with 6 μl (0.1 mmol) of thiobenzoicacid and 9 mg (0.03 mmol) of cesium carbonate, and stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure, and the residue obtained was treated with ethyl acetate,washed twice with water, twice with a saturated aqueous solution ofsodium hydrogen carbonate and then with saturated brine. The ethylacetate layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure, and the residue obtained was subjected to columnchromatography on silica gel eluting with ethyl acetate:hexane (8:92) toobtain 182 mg (yield: 82%) of3-benzoylthio-1-(4-phenoxybenzyl)piperidin-2-one as a pale red oil.

[0826]¹H-NMR (300 MHz, CDCl₃)

[0827] δ: 7.99-7.96 (2H, m), 7.60-6.95 (12H, m), 4.64 (1H, d, J=14.5Hz), 4.58 (1H, d, J=14.4 Hz), 4.51 (1H, dd, J=7.8, 5.8 Hz), 3.41-3.26(2H, m), 2.40-2.30 (1H, m), 2.11-1.86 (3H, m).

Example 48 3-Mercapto-1-(4-phenoxybenzyl)piperidin-2-one

[0828] 127 mg (0.04 mmol) of3-acethylthio-1-(4-phenoxybenzyl)piperidin-2-one obtained in Example 46was processed similarly to Example 29 to obtain 108 mg (yield: 96%) of3-mercapto-1-(4-phenoxybenzyl)piperidin-2-one as a brown oil.

[0829]¹H-NMR (300 MHz, CDCl₃)

[0830] δ: 7.37-6.94 (9H, m), 4.61 (1H, d, J=14.5 hz), 4.50 (1H, d,J=14.5 Hz), 3.84-3.78 (1H, m), 3.34-3.20 (2H, m), 2.60 (1H, d, J=4.2Hz), 2.28-1.70 (4H, m).

Example 49 S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]thiocarbamate

[0831] 400 mg (1.34 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 10 ml of chloroform, and added dropwise to asolution of 118.7 μl (1.47 mmol) of N-chlorocarbonyl isocyanate in 2 mlof chloroform at a temperature of −18 to −12° C., and after completionof the addition the mixture was stirred at the same temperature for 30minutes and then warmed to 0° C. over a period of 1 hour, and thenstirred at room temperature for 12 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith 6N hydrochloric acid and saturated brine, and then dried overanhydrous sodium sulfate. The mixture was concentrated under reducedpressure and purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:3)) to obtain 212 mg (yield: 46%) of the titlecompound as a white solid.

[0832]¹H-NMR (300 MHz, CDCl₃)

[0833] δ: 7.36-6.94 (9H, m), 5.59. (2H, br), 4.43 (2H, s), 4.08-4.03(1H, m), 3.78 (1H, dd, J=10.7, 7.3 Hz), 3.27 (1H, dd, J=10.7, 4.6 Hz),2.93 (1H, dd, J=17.4, 8.9 Hz), 2.47 (1H, dd, J=17.4, 5.7 Hz)

Example 50S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]methylthiocarbamate

[0834] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, and treated with 50 mg (0.88mmol) of methyl isocyanate and 0.5 μl (catalytic amount) oftriethylamine and then stirred under nitrogen atmosphere for 20 minutes.The reaction mixture was concentrated under reduced pressure, dissolvedin chloroform, washed with water, and then dried over anhydrous sodiumsulfate. The mixture was concentrated under reduced pressure andpurified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:2, 1:3)) and precipitated from n-hexane:ethylacetate to obtain 198 mg (yield: 76%) of the title compound as a whitepowder.

[0835] Elemental analysis (%): C₁₉H₂₀N₂O₃S·0.5H₂O

[0836] Calcd.: C, 62.44;H, 5.79;N, 7.6

[0837] Found: C, 62.46; H, 5.87; N, 7.66

Example 51S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]ethylthiocarbamate

[0838] Similarly to Example 50 and starting from 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 87.2 μl (1.10 mmol) of ethyl isocyanate and 13.9 μl (0.102 mmol) oftriethylamine, 122 mg (yield: 66%) of the title compound was obtained asa colorless needle.

[0839] Elemental analysis (%): C₂₀H₂₂N₂O₃S

[0840] Calcd.: C, 64.84; H, 5.99; N, 7.56

[0841] Found: C, 84.88; H, 6.04; N, 7.65

Example 52S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]propylcarbamothioate

[0842] Similarly to Example 50 and starting from 100 mg (0.33 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,34 μl (0.37 mmol) of propyl isocyanate and 47 μl (0.33 mmol) oftriethylamine, 110 mg (yield: 87%) of the title compound was obtained asa colorless needle.

[0843]¹H-NMR (200 MHz, CDCl₃)

[0844] δ: 7.40-6.90 (9H, m), 5.45-5.30 (1H, m), 4.43 (2H, s), 4.15-4.00(1H, m), 3.79 (1H, dd, J=7.4, 10.0 Hz), 3.27 (1H, dd, J=4.8, 10.0 Hz),3.30-3.15 (2H, m), 2.92 (1H, dd, J=8.8, 16.0 Hz), 2.46 (1H, dd, J=6.0,18.0 Hz), 1.65-1.45 (2H, m), 0.92 (3H, t, J=7.4 Hz)

Example 53S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]phenylcarbamothioate

[0845] Similarly to Example 50 and starting from 100 mg (0.33 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,36 μl (0.33 mmol) of phenyl isocyanate and 47 μl (0.33 mmol) oftriethylamine, 120 mg (yield: 87%) of the title compound was obtained asa colorless needle.

[0846]¹H-NMR (200 MHz, CDCl₃)

[0847] δ: 7.52-6.90 (15H, m), 4.45 (2H, s), 4.22-4.08 (1H, m), 3.85 (1H,dd, J=7.1, 12.0 Hz), 3.34 (1H, dd, J=4.2, 12.0 Hz), 2.98 (1H, dd, J=8.8,18.0 Hz), 2.53 (1H, dd, J=5.2, 18.0 Hz)

Example 54S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]benzylthiocarbamate

[0848] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 99 μl (0.80 mmol)of benzyl isocyanate and 0.5 μl (catalytic amount) of triethylamine andthen stirred under nitrogen atmosphere for 1 hour. The reaction mixturewas concentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: chloroform:methanol (20:1)) andprecipitated from n-hexane:ethyl acetate to obtain 217 mg (yield: 75%)of the title compound as a white powder.

[0849]¹H-NMR (300 MHz, CDCl₃)

[0850] δ: 7.37-6.94 (14H, m), 5.71 (1H, br), 4.40 (4H, bs), 4.15-4.06(1H, m), 3.79 (1H, dd, J=10.7, 7.3 Hz), 3.28 (1H, dd, J=10.7, 4.8 Hz),2.92 (1H, dd, J=17.4, 8.9 Hz), 2.46 (1H, dd, J=17.4, 6.0 Hz)

Example 55S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]acetylthiocarbamate

[0851] 264 mg (1.76 mmol) of silver cyanate and 125 μl (1.76 mmol) ofacetyl chloride were added to 4 ml of toluene, and the mixture wasstirred at 70° C. for 30 minutes. The reaction mixture was cooled, andthe supernatant was used to dissolve 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, to which 5.1 μl (catalytic amount) of triethylamine was added, andthe mixture was stirred at room temperature for 20 minutes. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed twice with water and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl ethyl acetate (1:2)) andprecipitated from n-hexane:ethyl acetate to obtain 193 mg (yield: 68%)of the title compound as a white powder.

[0852]¹H-NMR (300 MHz, CDCl₃)

[0853] δ: 8.40 (1H, s), 7.37-6.95 (9H, m), 4.44 (2H, s), 4.40 (4H, bs),4.12-4.02 (1H, m), 3.78 (1H, dd, J=10.7, 7.7 Hz), 3.26 (1H, dd, J=10.7,5.0 Hz), 2.95 (1H, dd, J=17.5, 9.1 Hz), 2.50 (1H, dd, J=17.5, 6.2 Hz),2.05 (3H, s)

Example 56S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]benzoylthiocarbamate

[0854] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 113 μl (0.81 mmol)of benzoyl isocyanate and 5.1 μl (catalytic amount) of triethylamine andthen stirred under nitrogen atmosphere for 30 minutes. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed twice with water and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain230 mg (yield: 70%) of the title compound as a colorless oil.

[0855]¹H-NMR (300 MHz, CDCl₃)

[0856] δ: 7.97-6.92 (14H, m), 4.47-4.32 (2H, m), 4.14-4.04 (1H, m), 3.79(1H, dd, J=10.7, 7.8 Hz), 3.29 (1H, dd, J=10.7, 5.1 Hz), 2.93 (1H, dd,J=17.5, 9.0 Hz), 2.51 (1H, dd, J=17.5, 6.2 Hz).

[0857] Example 57

O-EthylS-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]imidothiodicarbonate

[0858] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 93 μl (0.81 mmol)of ethyl isocyanatoformate and 5.1 μl (catalytic amount) oftriethylamine and then stirred under nitrogen atmosphere for 30 minutes.The reaction mixture was concentrated under reduced pressure andpurified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:2)) and precipitated from n-hexane:ethylacetate to obtain 214 mg (yield: 70%) of the title compound as a whitepowder.

[0859]¹H-NMR (300 MHz, CDCl₃)

[0860] δ: 7.69 (1H, bs), 7.37-6.94 (9H, m), 4.43 (2H, s), 4.24 (2H, q,J=7.1 Hz), 4.07-4.03 (1H, m), 3.79 (1H, dd, J=10.7, 7.7 Hz), 3.25 (1H,dd, J=10.7, 5.1 Hz), 2.94 (1H, dd, J=17.5, 9.1 Hz), 2.50 (1H, dd,J=17.5, 6.3 Hz), 1.31 (3H, t, J=7.1 Hz)

Example 58 Ethyl[({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)amino]acetate

[0861] Similarly to Example 50 and starting from 300 mg (1.00 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 246 μl (2.20 mmol) of ethyl isocyanatoacetate and 41.7 μl (0.300mmol) of triethylamine, 417 mg (yield: 97%) of the title compound wasobtained as a colorless oil.

[0862] Elemental analysis (%): C₂₂H₂₄N₂O₅S·0.44H₂O

[0863] Calcd.: C, 60.64; H, 5.74; N, 6.43

[0864] Found: C, 60.60; H, 5.70; N, 6.43

Example 59[({[(3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)amino]acetic acid

[0865] 225 mg (0.525 mmol) of ethyl[({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)amino]acetate obtained in Example 58 was dissolved in a mixture of 3 ml of aceticacid and 3 ml of conc. hydrochloric acid, and then heated at 100° C. for25 minutes with stirring. The reaction mixture was poured into an icedwater and extracted twice with ethyl acetate, and the ethyl acetatelayer was washed three times with water and once with saturated brine,and then dried over anhydrous sodium sulfate. After concentrating underreduced pressure followed by column chromatography on silica gel, thefraction eluted with chloroform:methanol (95:5) was concentrated andprecipitated from ether to obtain 123 mg (yield: 59%) of the titlecompound as a white powder.

[0866] Elemental analysis (%): C₂₀H₂₀N₂O₅S

[0867] Calcd.: C, 59.99; H, 5.03; N, 7.00

[0868] Found: C, 59.81; H, 4.92;N, 7.07 Example 60 Ethyl[({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)amino]propanoate

[0869] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 106 μl (0.80 mmol)of ethyl 3-isocyanatopropionate and 0.5 μl (catalytic amount) oftriethylamine and then stirred under nitrogen atmosphere for 30 minutes.The reaction mixture was concentrated under reduced pressure andpurified by preparative thin layer chromatography (eluent:chloroform:methanol (20:1)) to obtain 243 mg (yield: 82%) of the titlecompound as a colorless oil.

[0870]¹H-NMR (300 MHz, CDCl₃)

[0871] δ: 7.37-6.94 (9H, m), 5.94 (1H, br), 4.43 (2H, s), 4.16 (2H, q,J=7.1 Hz), 4.09-4.02 (1H, m), 3.76 (1H, dd, J=10.6, 7.5 Hz), 3.53 (2H,br) 3.25 (11, dd, J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.3, 8.9 Hz), 2.53(2H, t, J=5.9 Hz), 2.45 (1H, dd, J=17.4, 6.2 Hz), 1.26 (3H, t, J=7.1 Hz)

Example 61N-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)-p-alanine

[0872] 261 mg (0.59 mmol) of ethyl[({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}carbonyl)amino]propanoate was dissolved in 3 ml of a (1:1) mixture of conc. hydrochloricacid and acetic acid, and stirred at 100° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure, dissolved inethyl acetate, washed with 1N hydrochloric acid and saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: chloroform:methanol (10:1)) to obtain 170mg (yield: 70%) of the title compound as a colorless oil.

[0873]¹H-NMR (300 MHz, DMSO-d₆)

[0874] δ: 8.31 (1H, br), 7.42-6.95 (9H, m), 4.39 (1H, d, J=15.1 Hz),4.33 (1H, d, J=15.1 Hz), 3.98-3.90 (1H, n), 3.71 (1H, dd, J=10.4, 7.3Hz), 3.26 (2H, t, J=6.5 Hz), 3.16 (1H, dd, J=10.4, 4.5 Hz), 2.83 (1H,dd, J=17.0, 8.6 Hz), 2.36 (2H, t, J=6.9 Hz), 2.27 (1H, dd, J=17.0, 5.6Hz)

Example 62S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]dimethylcarbamothioate

[0875] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 68 μl (0.73 mmol) of N,N-dimethylcarbonyl chloride were dissolvedin 1 ml of chloroform, treated dropwise with a solution of 102 μl (0.73mmol) of triethylamine in 1 ml of chloroform at 0° C., and aftercompletion of the addition the mixture was stirred at room temperaturefor 1 hour. Subsequently, 27 mg (0.67 mmol) of 60% sodium hydride wasadded and the mixture was stirred at room temperature for 10 minutes,concentrated under reduced pressure, dissolved in ethyl acetate, washedtwice with water and then with saturated brine, and dried over anhydroussodium sulfate. The reaction mixture was concentrated under reducedpressure and purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 153 mg (yield: 62%) of the titlecompound as a pale yellow oil.

[0876] Elemental analysis (%): C₂₀H₂₂N₂O₃S·0.1H₂O

[0877] calcd.: C, 64.52; H, 6.01; N, 7.52

[0878] Found: C, 64.38; H, 6.05; N, 7.41

Example 63S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]4-morpholinecarbothioate

[0879] Similarly to Example 62 and starting from 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 451 μl (3.85 mmol) of morpholinecarbonyl chloride and 140 mg (3.50mmol) of 60% sodium hydride, 185 mg (yield: 90%) of the title compoundwas obtained as a colorless oil.

[0880] Elemental analysis (%): C₂₂H₂₄N₂O₄S·0.3H₂O

[0881] Calcd.: C, 63.23; H, 5.93; N, 6.70

[0882] Found: C, 63.09; H, 5.95; N, 6.66

Example 64 S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]propanethioate

[0883] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 64 μl (0.73 mmol) of propionyl chloride were dissolved in 2 ml ofchloroform, treated dropwise with a solution of 102 μl (0.73 mmol) oftriethylamine in 1 ml of chloroform at 0° C., and after completion ofthe addition the mixture was stirred at 0° C. for 1 hour. The mixturewas concentrated under reduced pressure, dissolved in ethyl acetate,washed with water and saturated brine, and dried over anhydrous sodiumsulfate. The reaction mixture was concentrated under reduced pressureand purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 228 mg (yield: 96%) of the titlecompound as a pale pinkish oil.

[0884]¹H-NMR (300 MHz, CDCl₃)

[0885] δ: 7.37-6.95 (9H, m), 4.46 (1H, d, J=14.7 Hz), 4.40 (1H, d,J=14.7 Hz), 4.10-4.01 (1H, m), 3.76 (1H, dd, J=10: 7, 7.5 Hz), 3.17 (1H,dd, J=10.7, 5.0 Hz), 2.92 (1H dd, J=17.4, 9.0 Hz), 2.55 (2H, t, J=7.5Hz), 2.42 (1H, dd, J=17.4, 6.0 Hz), 1.16 (3H, t, J=7.5 Hz)

Example 65 S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]butanethioate

[0886] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 76 μl (0.73 mmol) of butyryl chloride were dissolved in 2 ml ofchloroform, treated dropwise with a solution of 102 μl (0.73 mmol) oftriethylamine in 1 ml of chloroform at 0° C., and after completion ofthe addition the mixture was stirred at 0° C. for 1 hour. The mixturewas concentrated under reduced pressure, dissolved in ethyl acetate,washed with water and saturated brine, and dried over anhydrous sodiumsulfate. The reaction mixture was concentrated under reduced pressureand purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 228 mg (yield: 92%) of the titlecompound as a colorless oil.

[0887]¹H-NMR (300 MHz, CDCl₃)

[0888] δ: 7.37-6.95 (9H, m), 4.47 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 4.10-4.01 (1H, m), 3.76 (1H, dd, J=10.7, 7.5 Hz), 3.16 (1H,dd, J=10.7, 4.9 Hz), 2.92 (1H, dd, J=17.4, 8.9 Hz), 2.51 (2H, t, J=7.4Hz), 2.42 (1H, dd, J=17.4, 5.9 Hz), 1.73-1.60 (2H, m), 1.16 (3H, t,J=7.5 Hz)

Example 66 S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]pentanethioate

[0889] Similarly to Example 64 and starting from 100 mg (0.33 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,48 mg (0.40 mmol) of valeryl chloride and 57 μl (0.40 mmol) oftriethylamine, 78 mg (yield: 62%) of the title compound was obtained asa colorless oil.

[0890]¹H-NMR (200 MHz, CDCl₃)

[0891] δ: 7.40-6.90 (9H, m), 4.48 (1H, d, J=16.0 Hz), 4.40 (1H, d,J=14.0 Hz), 4.12-3.97 (1H, m), 3.77 (1H, dd, J=7.5, 10.0 Hz), 3.17 (1H,dd, J=4.9, 10.0 Hz), 2.93 (1H, dd, J=8.9, 16.0 Hz), 2.53 (2H, t, J=7.8Hz), 2.43 (1H, dd, J=6.0, 18.0 Hz), 1.70-1.55 (2H, m), 1.42-1.24 (2H,m), 0.90 (3H, t, J=7.3 Hz)

Example 67S-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]2-methylpropanethioate

[0892] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 77 μl (0.73 mmol) of isobutyryl chloride were dissolved in 2 mlof chloroform, treated dropwise with a solution of 102 μl (0.73 mmol) oftriethylamine in 1 ml of chloroform at 0° C., and after completion ofthe addition the mixture was stirred at 0° C. for 1 hour. The mixturewas concentrated under reduced pressure, dissolved in ethyl acetate,washed with water and saturated brine, and dried over anhydrous sodiumsulfate. The reaction mixture was concentrated under reduced pressureand purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 223 mg (yield: 91%) of the titlecompound as a colorless oil.

[0893]¹H-NMR (300 MHz, CDCl₃)

[0894] δ: 7.06-6.95 (9H, m), 4.47 (1H, d, J=14.6 Hz), 4.39 (1H, d,J=14.7 Hz), 4.07-3.73 (1H, m), 3.76 (1H, dd, J=10.6, 7.4 Hz), 3.15 (1H,dd, 3=10.6, 4.8 Hz), 2.92 (1H, dd, J=17.4, 8.9 Hz), 2.77-2.63 (1H, m),2.42 (1H, dd, J=17.4, 5.8 Hz), 1.19-1.15 (6H,

Example 68S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]2-phenylethanethioate

[0895] Similarly to Example 64 and starting from 100 mg (0.33 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,57 mg (0.37 mmol) of phenylacetyl chloride and 57 μl (0.40 mmol) oftriethylamine, 61 mg (yield: 44%) of the title compound was obtained asa colorless oil.

[0896]¹H-NM (200 MHz, CDCl₃)

[0897] δ: 7.40-6.90 (14H, m), 4.45 (1H, d, J=14.8 Hz), 4.36 (1H, d,J=14.7 Hz), 4.10-3.95 (1H, m), 3.79 (2H, s), 3.74 (1H, dd, J=7.5, 10.0Hz), 3.14 (1H, dd, J=4.9, 10.0 Hz), 2.90 (1H, dd, J=9.0, 18.0 Hz), 2.40(1H, dd, J=6.1, 18.0 Hz)

Example 69S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]-(4-chlorophenyl)ethanethioate

[0898] Similarly to Example 64 and starting from 100 mg (0.33 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,76 mg (0.40 mmol) of p-chlorophenylacetyl chloride and 57 μl (0.40 mmol)of triethylamine, 85 mg (yield: 57%) of the title compound was obtainedas a colorless oil.

[0899]¹H-NMR (200 MHz, CDCl₃)

[0900] δ: 7.40-6.90 (13H, n), 4.45 (1H, d, J=14.7 Hz), 4.37 (1H, d,J=14.7 Hz), 4.10-3.95 (1H, m), 3.75 (2H, s), 3.74 (1H, dd, J=7.5, 10.0Hz), 3.13 (1H, dd, J=4.9, 12.0 Hz), 2.90 (1H, dd, J=8.8, 18.0 Hz), 2.38(1H, dd, J=5.9, 20.0 Hz)

Example 70 S-[5-oxo-1-(4-phenoxybenzyl)-3-pyrrolidinyl]2,2-diphenylethanethioate

[0901] Similarly to Example 64 and starting from 50 mg (0.17 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,58 mg (0.25 mmol) of diphenylacetyl chloride and 57 μl (0.40 mmol) oftriethylamine, 57 mg (yield: 69%) of the title compound was obtained asa colorless oil.

[0902]¹H-NMR (200 MHz, CDCl₃)

[0903] δ: 7.40-6.90 (19H, m), 5.13 (1H, s), 4.45 (1H, d, J=14.5 Hz),4.36 (1H, d, J=14.7 Hz), 4.14-4.00 (1H, m), 3.77 (1H, dd, J=7.4, 10.0Hz), 3.16 (1H, dd, J=4.8, 12.0 Hz), 2.92 (1H, dd, J=8.9, 18.0 Hz), 2.41(1H, dd, J=5.9, 18.0 Hz)

Example 71 Ethyl3-oxo-3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoate

[0904] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 94 μl (0.73 mmol) of ethyl-3-chloro-3-oxoropionate were dissolvedin 1 ml of chloroform, treated dropwise with a solution of 102 μl (0.73mmol) of triethylamine in 1 ml of chloroform at 0° C., and aftercompletion of the addition the mixture was stirred at 0° C. for 1 hour.The mixture was concentrated under reduced pressure, dissolved in ethylacetate, washed twice with water and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain175 mg (yield: 63%) of the title compound as a colorless oil.

[0905]¹H-NMR (300 MHz, CDCl₃)

[0906] δ: 7.37-6.95 (9H, m), 4.43 (2H, s), 4.19 (2H, q, J=7.1 Hz),4.14-4.09 (1H, m), 3.78 (1H, dd, J=10.7, 7.5 Hz), 3.55 (2H, s), 3.20(1H, dd, J=10.7, 4.8 Hz), 2.94 (1H, dd, J=17.4, 8.9 Hz), 2.44 (1H, dd,J=17.4, 5.9 Hz), 1.27 (3H, t, J=7.1 Hz)

Example 72 t-Butyl3-oxo-3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoate

[0907] 124 μl (0.73 mmol) of mono-t-butyl malonate was dissolved in 1 mlof acetonitrile, and 130 mg (0.73 mmol) of N,N-carbonyldiimidazole wasadded, and the mixture was stirred for 1 hour, and then a solution of200 mg (0.67 mmol) of (R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 25 in 1 ml of acetonitrile was added and the mixturewas stirred for 10 minutes. The reaction mixture was concentrated underreduced pressure, dissolved in ethyl acetate, washed twice with 0.1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure and purified by preparative thin layer chromatography(eluent: n-hexane:ethyl acetate (1:2)) to obtain 180 mg (yield: 61%) ofthe title compound as a colorless oil.

[0908]¹H-NMR (300 MHz, CDCl₃)

[0909] δ: 7.37-6.95 (9H, m), 4.43 (2H, s), 4.14-4.06 (1H, m), 3.78 (1H,dd, J=10.7, 7.5 Hz), 3.47 (2H, s), 3.20 (1H, dd, J=10.7, 4.8 Hz), 2.93(1H, dd, J=17.4, 9.0 Hz), 2.44 (1H, dd, J=17.4, 5.9 Hz), 1.53 (9H, s)

Example 733-Oxo-3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoicacid

[0910] 224 mg (0.51 mmol) of t-butyl3-oxo-3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoateobtained in Example 72 and 203 μl (1.28 mmol) of triethylsilane weredissolved in a mixture of 2 ml of acetic acid and 2 ml of chloroform,and stirred for 5 days. The reaction mixture was concentrated underreduced pressure, dissolved in ethyl acetate, washed with 1Nhydrochloric acid and then with a mixture of 1 N hydrochloric andsaturated brine, and dried over anhydrous sodium sulfate. The reactionmixture was concentrated under reduced pressure and precipitated fromethyl acetate to obtain 151 mg (yield: 77%) of the title compound as awhite powder.

[0911]¹H-NMR (300 MHz, DMSO-d₆)

[0912] δ: 7.42-6.97 (91 m), 4.40 (1H, d, J=15.1 Hz), 4.35 (1H, d, J=15.1Hz), 4.11-4.02 (1H, m), 3.76 (1H, dd, J=10.6, 7.4 Hz), 3.66 (2H, s),3.16 (1H, dd, J=10.6, 4.3 Hz), 2.90 (1H, dd, J=17.1, 8.8 Hz), 2.30 (1H,dd, J=17.1, 5.2 Hz)

Example 74 Ethyl4-oxo-4-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}butanoate

[0913] 113 μl (0.88 mmol) of monoethyl succinate was dissolved in 1 mlof acetonitrile, and 130 mg (0.73 mmol) of N,N-carbonyldiimidazole wasadded, and the mixture was stirred for 30 minutes, and then a solutionof 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 in 1 ml of acetonitrile was added and the mixture was stirred for 10minutes. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with 1 N hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thereaction mixture was concentrated under reduced pressure and purified bypreparative thin layer chromatography (eluent: n-hexane:ethyl acetate(1:2)) to obtain 236 mg (yield: 75%) of the title compound as a whitesolid.

[0914]¹H-NMR (300 MHz, CDCl₃)

[0915] δ: 7.37-6.95 (9H, m), 4.43 (2H, s), 4.11-4.04 (3H, m), 3.75 (1H,dd, J=10.6, 7.5 Hz), 3.17 (1 dd, J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.4,8.9 Hz), 2.86 (2H, t, J=7.1 Hz), 2.62 (2H, t, J=6.9 Hz), 2.42 (1H, dd,J=17.4, 6.0 Hz), 1.24 (3H, t, J=7.1 Hz)

Example 754-Oxo-4-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}butanoicacid

[0916] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 67 mg (0.67 mmol) of succinic anhydride were dissolved in 2 ml ofTHF, and 27 mg (0.67 mmol) of 60% sodium hydride was added, and themixture was stirred at room temperature for 16 hours. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed with 1 N hydrochloric acid and then with saturatedbrine, and dried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:chloroform:methanol (5:1)) to obtain 163 mg(yield: 61%) of the title compound as a pale brown oil.

[0917] Elemental analysis (%): C₂₁H₂₁NO₅S·0.1H₂O

[0918] Calcd.: C, 62.85; H, 5.32; N, 3.49

[0919] Found: C, 62.80; H, 5.12; N, 3.52

Example 76 (3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinylmethyldithiocarbonate

[0920] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 59 mg (0.81 mmol)of methyl isothocyanate and 5.1 μl (catalytic amount) of triethylamine,and stirred under nitrogen atmosphere for 12 hours. The reaction mixturewas concentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain 75mg (yield: 27%) of the title compound as a colorless oil.

[0921]¹H-NMR (300 MHz, CDCl₃)

[0922] δ: 8.30-7.98 (1H, m), 7.35-6.92 (9H, m), 4.56-4.49 (1H, m), 4.44(1H, d, J=14.8 Hz), 4.36 (1H, d, J=14.7 Hz), 3.89 (1H, dd, J=11.1, 6.9Hz), 3.37 (1H, dd, J=1.1, 3.0 Hz), 3.19 (3H, d, J=7.8 Hz), 3.02 (1H, dd,J=17.9, 8.9 Hz), 2.55 (1H, dd, J=17.7, 4.0 Hz)

Example 77 (3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinylethyldithiocarbonate

[0923] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of chloroform, treated with 71>1 (0.81 mmol) ofethyl isothocyanate and a previously prepared solution of 5.1 μl(catalytic amount) of triethylamine and 2.1 μl (catalytic amount) ofacetic acid in 0.1 ml of chloroform, and stirred under nitrogenatmosphere for 2 days. The reaction mixture was concentrated underreduced pressure, dissolved in ethyl acetate, washed with 0.1 Nhydrochloric acid and then with saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure and purified by preparative thin layer chromatography(eluent: n-hexane:ethyl acetate (1:2)) to obtain 211 mg (yield: 74%) ofthe title compound as a pale pinkish oil.

[0924]¹H-NMR (300 MHz, CDCl₃)

[0925] δ: 7.61-6.91 (10H, m), 4.51-4.38 (3H, m), 3.91-3.84 (1H, m),3.74-3.32 (3H, m), 3.06-2.97 (1H, m), 2.55-2.48 (1H, m), 1.26 (3H, t,J=7.2 Hz)

Example 78(4R)-4-[(Methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidine

[0926] 50 mg (0.17 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 1 ml of methanol, and 17 μl (0.18 mmol) ofmethoxycarbonylsulfenyl chloride was added and the mixture was stirredat room temperature for 1 hour. The reaction mixture was concentratedunder reduced pressure, dissolved in ethyl acetate, washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thereaction mixture was concentrated under reduced pressure to obtain 62 mg(yield: 95%) of the title compound as a pale brown oil.

[0927] Elemental analysis (%): C₁₉H₁₉NO₄S₂

[0928] Calcd.: C, 58.59; H, 4.92; N, 3.60

[0929] Found: C, 58.29; H, 4.95; N, 3.61

Example 79 (4R)-4-(Ethyldisulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0930] 220 mg (0.57 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in a mixture of 1 ml of chloroformand 1 ml of methanol, treated with 209 μl (2.82 mmol) of ethanethiol and0.4 μl (catalytic amount) of triethylamine, and stirred under nitrogenatmosphere at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The reaction mixture was concentrated under reduced pressure andpurified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 140 mg (yield: 69%) of the titlecompound as a colorless oil.

[0931] Elemental analysis (%): C₁₉H₂₁NO₂S₂

[0932] Calcd.: C, 63.48; H, 5.89; N, 3.90

[0933] Found: C, 63.31; H, 5.91; N, 4.09

Example 80 (4R)-4-(Hexyldisulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0934] 200 mg (0.51 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in a mixture of 1 ml of chloroformand 1 ml of methanol, treated with 362 μl (2.57 mmol) of 1-hexanethioland 0.4 μl (catalytic amount) of triethylamine, and stirred undernitrogen atmosphere at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed with water, 0.1 N hydrochloric acid and saturated brine,and dried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:1)) to obtain157 mg (yield: 74%) of the title compound as a colorless oil.

[0935]¹H-NMR (300 MHz, CDCl₃)

[0936] δ: 7.37-6.96 (9H, m), 4.47 (1H, d, J=14.7 Hz), 4.41 (1H, d,J=14.7 Hz), 3.64-3.51 (2H, n), 3.33 (1H, dd, J=9.9, 3.5 Hz), 2.83 (1H,dd, J=17.4, 8.0 Hz), 2.65 (1H, t, J=7.3 Hz), 2.56 (1H, dd, J=17.5, 4.8Hz), 1.68-1.57 (2H, m), 1.40-1.27 (6H, m), 0.88 (3H, t, J=6.7 Hz)

Example 81(4R)-4-(t-Butyldisulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0937] 220 mg (0.57 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in a mixture of 1 ml of chloroformand 1 ml of methanol, treated with 319 μl (2.83 mmol) of2-methyl-2-propanethiol and 0.4 μl (catalytic amount) of triethylamine,and stirred under nitrogen atmosphere at room temperature for 30minutes. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with water and saturated brine,and dried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain183 mg (yield: 84%) of the title compound as a white solid.

[0938] Elemental analysis (%): C₂₁H₂₅NO₂S₂

[0939] calcd.: C, 65.08; H, 6.50; N, 3.61

[0940] Found: C, 65.02; H, 6.26; N, 3.65

Example 82 Ethyl2-{[(3R)-5-oxo-1-(4-phenoxybenzyl)-2-pyrrolidinyl]disulfanyl}acetate

[0941] 220 mg (0.57 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in a mixture of 1 ml of chloroformand 1 ml of methanol, treated with 68 μl (0.62 mmol) of ethyl2-mercaptoacetate and 0.4 μl (catalytic amount) of triethylamine, andstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate,filtered to remove insolubles, washed with water and saturated brine,and dried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain 51mg (yield: 22%) of the title compound as a colorless oil.

[0942] Elemental analysis (%): C₂₁H₂₃NO₄S₂

[0943] Calcd.: C, 60.41; H, 5.55; N, 3.35

[0944] Found: C, 60.32; H, 5.53; N, 3.45

Example 832-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)-2-pyrrolidinyl]disulfanyl}acetic acid

[0945] 220 mg (0.57 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in 2 ml of methanol, treated with39>1 (0.57 mmol) of mercaptobutyric acid and 0.8 μl (catalytic amount)of triethylamine, and stirred at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure, dissolved inethyl acetate, washed with 0.1 N hydrochloric acid, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure, purified by preparative thin layer chromatography(eluent: chloroform:methanol (5:1)) and precipitated from ethyl acetateto obtain 136 mg (yield: 62%) of the title compound as a white powder.

[0946]¹H-NMR (300 MHz, DMSO-d₆)

[0947] δ: 7.41-6.97 (9H, m), 4.43 (1H, d, J=14.8 Hz), 4.32 (1H, d,J=14.8 Hz), 3.86-3.16 (7H, n), 2.85 (1H, dd, J=17.4, 8.2 Hz), 2.31 (1H,dd, J=17.4, 3.7 Hz)

Example 84 Ethyl3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)-2-pyrrolidinyl]disulfanyl}propanoate

[0948] 220 mg (0.57 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in a mixture of 1 ml of chloroformand 1 ml of methanol, treated with 332 μl (2.57 mmol) of ethyl3-mercaptopropionate and 0.4 μl (catalytic amount) of triethylamine, andstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith 0.1 N hydrochloric acid and saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure and purified by preparative thin layer chromatography(eluent: n-hexane:ethyl acetate (1:2)) to obtain 72 mg (yield: 33%) ofthe title compound as a colorless oil.

[0949]¹H-NMR (300 MHz, CDCl₃)

[0950] δ: 7.36-6.95 (9H, m), 4.47 (1H, d, J=14.7 Hz), 4.40 (1H, d,J=14.7 Hz), 4.14 (2H, q, J=7.1 Hz), 3.65-3.54 (2H, m), 3.36-3.30 (1H,m), 2.92-2.79 (3H, m), 2.68 (2H, t, J=7.0 Hz), 2.52 (1H, dd, J=17.5, 4.4Hz), 1.26 (3H, t, J=7.0 Hz)

Example 853-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)-2-pyrrolidinyl]disulfanyl}propanoicacid

[0951] 200 mg (0.51 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in 2 ml of methanol, treated with45 μl (0.51 mmol) of 3-mercaptopropionic acid and 0.4 μl (catalyticamount) of triethylamine, and stirred at room temperature for 4 hours.The reaction mixture was concentrated under reduced pressure andpurified by preparative thin layer chromatography (eluent:chloroform:methanol (10:1)) to obtain 188 mg (yield: 91%) of the titlecompound as a colorless oil.

[0952]¹H-NMR (300 MHz, DMSO-d₆)

[0953] δ: 7.41-6.95 (9H, m), 4.43 (1H, d, J=14.8 Hz), 4.31 (1H, d,J=14.9 Hz), 3.78-3.71 (1H, m), 3.65 (1H, dd, J=10.7, 6.7 Hz), 3.25 (1H,dd, J=10.7, 2.9 Hz), 2.89-2.78 (3H, m), 2.57 (2H, t, J=6.8 Hz), 2.31(1H, dd, J=17.3, 3.8 Hz),

Example 862-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)-1-pyrrolidinyl]disulfanyl}propanoicacid

[0954] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 3 ml of 95% ethanol, and 226 mg (0.67 mmol) ofO-carboxyphenyl O-carboxybenzenethiol sulfonate was added, and themixture was stirred at room temperature for 12 hours. The reactionmixture was concentrated under reduced pressure, dissolved inchloroform, filtered to remove insolubles, and purified by preparativethin layer chromatography (eluent:chloroform:methanol (8:1)) to obtain185 mg (yield: 61%) of the title compound as a colorless oil.

[0955] Elemental analysis (%): C₂₄H₂₁NO₄S₂·0.25H₂O

[0956] Calcd.: C, 63.20; H, 4.75; N, 3.07

[0957] Found: C, 63.05; H, 4.66; N, 2.97

Example 87(4R)-4-[(2-Nitrophenyl)disulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0958] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 2 ml of acetic acid, and 133 mg (0.70 mmol) of2-nitrobenzenesulfenyl chloride was added, and the mixture was stirredat room temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedtwice with water and then with saturated brine, and purified bypreparative thin layer chromatography (eluent:n-hexane:ethyl acetate(1:2)) to obtain 272 mg (yield: 90%) of the title compound as a paleyellow oil.

[0959] Elemental analysis (%): C₂₃H₂₀N₂O₄S₂

[0960] Calcd.: C, 61.04; H, 4.45; N, 6.19

[0961] Found: C, 60.99; H, 4.51; N, 6.05

Example 88(4-Amino-2-methyl-5-pyrimidinyl)methyl((Z)-4-hydroxy-1-methyl-2-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]disulfanyl}-1-butenyl)formamide

[0962] 100 mg (0.26 mmol) of(4R)-4-[(methoxycarbonyl)disulfanyl]-2-oxo-1-(4-phenoxybenzyl)pyrrolidineobtained in Example 78 was dissolved in 1 ml of ethanol, added to amixture of 87 mg (0.26 mmol) of thiamine hydrochloride, 77 μl (0.77mmol) of a 10 N aqueous solution of sodium hydroxide, 15 μl (0.26 mmol)of acetic acid and 1 ml of ethanol, and stirred at room temperature for20 minutes. The reaction mixture was concentrated under reducedpressure, dissolved in ethyl acetate, washed with a saturated aqueoussolution of sodium hydrogen carbonate and saturated brine, and driedover anhydrous sodium sulfate. The reaction mixture was concentratedunder reduced pressure and purified by preparative thin layerchromatography (eluent:chloroform:methanol (10:1)) to obtain 68 mg(yield: 45%) of the title compound as a white foam.

[0963] Elemental analysis (%): C₂₉H₃₃N₅O₄S₂·0.5H₂O

[0964] Calcd.: C, 59.16; H, 5.82; N, 11.89

[0965] Found: C, 59.14; H, 5.99; N, 11.97

Example 89 (4R)-4-(Methylsulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0966] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 50 μl (0.81 mmol) of iodomethane were dissolved in 2 ml of THF,treated with 29 mg (0.74 mmol) of 60% sodium hydride, and stirred undernitrogen atmosphere at room temperature for 10 minutes. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed with 0.1 N hydrochloric acid and saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 180mg (yield: 78%) of the title compound as a colorless oil.

[0967] Elemental analysis (%): C₁₈H₁₉NO₂S

[0968] Calcd.: C, 68.98; H, 6.11; N, 4.47

[0969] Found: C, 68.80; H, 6.00; N, 4.57

Example 90(4R)-4-[(2-Hydroxyethyl)sulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0970] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 47 μl (0.67 mmol) of 2-bromoethanol were dissolved in 2 ml ofTHF, treated with 27 mg (0.67 mmol) of 60% sodium hydride, and stirredat room temperature for 10 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith 1 N hydrochloric acid and saturated brine, and dried over anhydroussodium sulfate. The reaction mixture was concentrated under reducedpressure and purified by preparative thin layer chromatography(eluent:chloroform:methanol (15:1)) to obtain 149 mg (yield: 65%) of thetitle compound as a pale brown oil.

[0971] Elemental analysis (%): C₁₉H₂₁NO₃S

[0972] Calcd.: C, 66.45; H, 6.16; N, 4.08

[0973] Found: C, 66.30; H, 6.08; N, 4.05

Example 912-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}acetic acid

[0974] 199 mg (0.66 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 47 mg (0.66 mmol) of bromoacetic acid were dissolved in 2 ml ofTHF, treated with 27 mg (1.33 mmol) of 60% sodium hydride, and stirredat room temperature for 10 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedtwice with 1 N hydrochloric acid and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:chloroform:methanol (1:3)) to obtain 138 mg(yield: 58%) of the title compound as a pale brown oil.

[0975] Elemental analysis (%): Cl₁₉H₁₉NO₄S·0.8H₂O

[0976] Calcd.: C, 61.37; H, 5.58; N, 3.76

[0977] Found: C, 61.15; H, 5.32; N, 3.95

Example 92 Ethyl3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoate

[0978] Similarly to Example 89 and starting from 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 70.7 μl (0.551 mmol) of ethyl 3-bromopropionate and 20.0 mg (0.501mmol) of 60% sodium hydride, 145 mg (yield: 72%) of the title compoundwas obtained as a colorless oil.

[0979]¹H-NMR (300 MHz, CDCl₃)

[0980] δ: 7.34 (2H, m), 7.20 (2H, d, J=8.3 Hz), 7.11 (1H, m), 7.01 (2H,m), 6.97 (2H, d, J=8.3 Hz), 4.43 (2H, s), 4.15 (1H, q, J=7.2 Hz), 3.61(1H, dd, J=10.2, 7.5 Hz), 3.49 (1H, m), 3.19 (1H, dd, J=10.2, 5.3 Hz),2.86 (1H, dd, J=17.0, 8.3 Hz), 2.79 (2H, t, J=7.2 Hz), 2.57 (2H, t,J=7.2 Hz), 2.43 (1H, dd, J=17.0, 6.4 Hz), 1.26 (3H, t, J=7.2 Hz)

Example 933-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}propanoic acid

[0981] Similarly to Example 89 and starting from 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 76.6 μl (0.501 mmol) of 3-bromopropionic acid and 40.1 mg (1.00mmol) of 60% sodium hydride, 71.5 mg (yield: 38%) of the title compoundwas obtained as a white powder.

[0982]¹H-NMR (300 MHz, CDCl₃)

[0983] δ: 7.34 (2H, m), 7.20 (2H, d, J=8.5 Hz), 7.11 (1H, m), 7.00 (2H,m), 6.96 (2H, d, J=8.5 Hz), 4.43 (2H, s), 3.62 (1H, dd, J=10.0, 7.7 Hz),3.51 (1H, m), 3.19 (1H, dd, J=10.0, 5.1 Hz), 2.88 (1H, dd, J=17.3, 8.3Hz), 2.79 (2H, t, J=7.1 Hz), 2.63 (2H, t, J=7.1 Hz), 2.47 (1H, dd,J=17.3, 6.0 Hz)

Example 944-[(4-Bromobenzyl)sulfanyl)-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0984] Similarly to Example 89 and starting from 80 mg (0.27 mmol) of4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example 17,67 mg (0.27 mmol) of p-bromobenzyl bromide and 12 mg (0.30 mmol) of 60%sodium hydride, 110 mg (yield: 87.9%) of the title compound was obtainedas a colorless oil.

[0985]¹H-NMR (200 MHz, CDCl₃)

[0986] δ: 7.45-6.90 (13H, m), 4.44 (1H, d, J=14.6 Hz), 4.35 (1H, d,J=14.7 Hz), 3.67 (2H, s), 3.46 (1H, dd, J=7.3, 8.0 Hz), 3.32-3.19 (1H,m), 3.10 (1H, dd, J=5.2, 10.0 Hz), 2.76 (1H, dd, J=8.4, 18.0 Hz), 2.39(1H, dd, J=6.2, 22.0 Hz)

Example 95 Methyl4-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)benzoate

[0987] 500 mg (1.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 383 mg (1.67 mmol) of methyl 4-(bromomethyl)benzoate weredissolved in 5 ml of THF, treated with 67 mg (1.67 mmol) of 60% sodiumhydride, and stirred under nitrogen atmosphere at room temperature for10 minutes. The reaction mixture was concentrated under reducedpressure, dissolved in ethyl acetate, washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by columnchromatography on silica gel, and the fraction eluted withn-hexane:ethyl acetate (2:1 to 1:1) was concentrated to obtain 645 mg(yield: 86%) of the title compound as a yellow oil.

[0988] Elemental analysis (%): C₂₆H₂₅NO₄S

[0989] Calcd.: C, 69.78; H, 5.63; N, 3.13

[0990] Found: C, 69.64; H, 5.72; N, 3.35

Example 964-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)benzoicacid

[0991] 250 mg (0.56 mmol) of methyl4-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)benzoateobtained in Example 95 and 234 mg (5.59 mmol) of lithium hydroxidemonohydrate was stirred at room temperature for 1 hour in a mixture of 2ml of methanol, 1 ml of water and 1.5 ml of THF. The reaction mixturewas treated with ethyl acetate, washed with 1 N hydrochloric acid andthen with a mixture of 1 N hydrochloric acid and saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:chloroform:methanol (8:1)) to obtain 178 mg(yield: 73%) of the title compound as a colorless glassy substance.

[0992] Elemental analysis (%): C₂₅H₂₃NO₄S-0.1H₂O

[0993] Calcd.: C, 68.97; H, 5.37; N, 3.21

[0994] Found: C, 68.89; H, 5.32; N, 3.35

Example 971-(4-phenoxybenzyl)-4-{[2-(phenylsulfonyl)ethyl]sulfanyl}-2-pyrrolidinone

[0995] 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 15 ml of THF, cooled on ice, combined under argongas atmosphere with 168 mg (1.00 mmol) of phenylvinylsulfonic acid and56.0 μl (0.400 mmol) of triethylamine, and stirred for 48 hours at roomtemperature. The reaction mixture was treated with ethyl acetate, washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The reaction mixture was concentrated under reduced pressure andsubjected to column chromatography on silica gel, and the fractioneluted with hexane:ethyl acetate (20:80-10:90) was concentrated underreduced pressure and precipitated from diethyl ether to obtain 101 mg(yield: 43%) of the title compound as a white powder.

[0996] Elemental analysis (%): C₂₅H₂₅NO₄S₂

[0997] Calcd.: C, 64.21; H, 5.39; N, 3.00

[0998] Found: C, 64.18; H, 5.61; N, 2.99

Example 98(4R)-4-[(Methoxymethyl)sulfanyl]-1-(4-phenoxybenzyl)-2-pyrrolidinone

[0999] Similarly to Example 64 and starting from 150 mg (0.501 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25, 190 μl (2.51 mmol) of chloromethylether and 349 μl (2.51 mmol) oftriethylamine, 158 mg (yield: 92%) of the title compound was obtained asa colorless oil.

[1000] Elemental analysis (%): C₁₉H₂₁NO₃S

[1001] Calcd.: C, 66.45; H, 6.61; N, 4.08

[1002] Found: C, 66.53; H, 5.87; N, 4.41

Example 99(4R)-4-[(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)sulfanyl]-1-(4-phenoxybenzyl)-2-pyrrolidinone

[1003] 180 mg (0.60 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 99.3 mg (0.66 mmol) of O-formylbenzenebenzoic acid were dissolvedin 2 ml of trifluoroacetic acid, and stirred at room temperature for 17hours. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with an saturated aqueoussolution of sodium hydrogen carbonate and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 224mg (yield: 86%) of the title compound as a colorless oil.

[1004] Elemental analysis (%): C₂₅H₂₁NO₄S

[1005] Calcd.: C, 69.59; H, 4.91; N, 3.25

[1006] Found: C, 69.83; H, 4.82; N, 3.35

Example 100N-({[(3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)acetamide

[1007] 180 mg (0.60 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 58.9 mg (0.66 mmol) of acetamidemethanol were dissolved in 1 mlof trifluoroacetic acid, and stirred at room temperature for 30 minutes.The reaction mixture was concentrated under reduced pressure, dissolvedin ethyl acetate, washed twice with an saturated aqueous solution ofsodium hydrogen carbonate and then with saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure and purified by preparative thin layer chromatography(eluent:chloroform:methanol (9:1)) to obtain 167 mg (yield: 75%) of thetitle compound as a pale brown oil.

[1008] Elemental analysis (%): C₂₀H₂₂N₂O₃S

[1009] Calcd.: C, 64.84; H, 5.99; N, 7.56

[1010] Found: C, 64.89; H, 6.26; N, 7.76

Example 1012,2-Dimethyl-N-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)propanamide

[1011] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 108.1 mg (0.81 mmol) of N-hydroxyacetamidemethanol were dissolvedin 2 ml of trifluoroacetic acid, and stirred at room temperature for 10minutes. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with an saturated aqueoussolution of sodium hydrogen carbonate and then with saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 209mg (yield: 69%) of the title compound as a pale brown oil.

[1012] Elemental analysis (%): C₂₃H₂₈N₂O₃S·0.1H₂O

[1013] Calcd.: C, 66.67; H, 6.85; N, 6.76

[1014] Found: C, 66.55; H, 6.94; N, 6.67

Example 102N-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)benzamide

[1015] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 116.7 mg (0.77 mmol) of N-hydroxybenzamidemethanol were dissolvedin 2 ml of trifluoroacetic acid, and stirred at room temperature for 10minutes. The reaction mixture was concentrated under reduced pressure,purified by preparative thin layer chromatography (eluent:n-hexane:ethylacetate (1:3)) and precipitated from ethyl acetate to obtain 172 mg(yield: 54%) of the title compound as a white powder.

[1016] Elemental analysis (%): C₂₅H₂₄N₂O₃S·0.1H₂O

[1017] Calcd.: C, 69.13; H, 5.61; N, 6.44

[1018] Found: C, 69.11; H, 5.61; N, 6.34

Example 103 Ethyl{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methylcarbamate

[1019] 200 mg (0.67 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 88 mg (0.73 mmol) of N-(hydroxymethyl)urethane were dissolved in2 ml of trifluoroacetic acid, and stirred at room temperature for 10minutes. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed with water and saturated brine, anddried over anhydrous sodium sulfate. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 177mg (yield: 66%) of the title compound as a pale yellow oil.

[1020] Elemental analysis (%): C₂₁H₂₄N₂O₄S·0.1H₂O

[1021] Calcd.: C, 62.69; H, 6.06; N, 6.96

[1022] Found: C, 62.45; H, 6.07; N, 6.91

Example 1042-({[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}methyl)-1H-isoindole-1,3-(2H)-dione

[1023] 220 mg (0.74 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 and 176 mg (0.74 mmol) of N-(bromomethyl)phthalimide were dissolvedin 2 ml of THF; treated with 29 mg (0.74 mmol) of 60% sodium hydride andstirred at room temperature under nitrogen atmosphere for 50 minutes.The reaction mixture was concentrated under reduced pressure, dissolvedin ethyl acetate, washed twice with 0.1 N hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thereaction mixture was concentrated under reduced pressure and purified bypreparative thin layer chromatography (eluent:n-hexane:ethyl acetate(1:2)) to obtain 253 mg (yield: 75%) of the title compound as acolorless oil.

[1024] Elemental analysis (%): C₂₆H₂₂N₂O₄S·0.1H₂O

[1025] Calcd.: C, 67.83; H, 4.86; N, 6.08

[1026] Found: C, 67.74; H, 4.97; N, 6.05

Example 1053-{[(3R)-5-Oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}-2,5-pyrrolidinedione

[1027] 150 mg (0.50 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 1.5 ml of chloroform, treated with 54 mg (0.55 mmol)of maleimide and 7 μl (catalytic amount) of triethylamine, and stirredat room temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure, dissolved in ethyl acetate, washed twice withwater and then with saturated brine, and dried over anhydrous sodiumsulfate. The reaction mixture was concentrated under reduced pressureand purified by preparative thin layer chromatography (eluent:chloroform:methanol (8:1)) to obtain 165 mg (yield: 83%) of the titlecompound as a milky white powder.

[1028] Elemental analysis (%): C₂₁H₂₀N₂O₄S·0.2H₂O

[1029] Calcd.: C, 63.04; H, 5.13; N, 7.00

[1030] Found: C, 63.00; H, 4.99; N, 6.94

Example 1061-Methyl-3-{[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]sulfanyl}-2,5-pyrrolidinedione

[1031] 150 mg (0.50-mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 1.5 ml of chloroform, treated with 61 mg (0.55 mmol)of N-methylmaleimide and 7 μl (catalytic amount) of triethylamine, andstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedthree times with water and then with saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure and purified by preparative thin layer chromatography(eluent:chloroform:methanol (15:1)) to obtain 155 mg (yield: 75%) of thetitle compound as a pale yellow oil.

[1032] Elemental analysis (%): C₂₂H₂₂N₂O₄S·0.3H₂O

[1033] Calcd.: C, 63.53; H, 5.47; N, 6.73

[1034] Found: C, 63.28; H, 5.40; N, 6.50

Example 107 O-EthylS-[(3R)-5-oxo-1-(4-phenoxybenzyl)pyrrolidinyl]carbanothioate

[1035] 180 mg (0.60 mmol) of(R)-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one obtained in Example25 was dissolved in 1 ml of chloroform, and 63 μl (0.66 mmol) of ethylchloroformate at 0° C. was added and then a solution of 92 μl (0.66mmol) of triethylamine in 1 ml of chloroform was added dropwise, andafter completion of the addition the mixture was stirred at 0° C. for 1hour. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with water and then withsaturated brine, and dried over anhydrous sodium sulfate. The reactionmixture was concentrated under reduced pressure and purified bypreparative thin layer chromatography (eluent:n-hexane:ethyl acetate(1:2)) to obtain 184 mg (yield: 83%) of the title compound as a paleyellow oil.

[1036] Elemental analysis (%): C₂₀H₂₁NO₄S·0.1H₂O

[1037] Calcd.: C, 64.35; H, 5.72; N, 3.75

[1038] Found: C, 64.15; H, 5.71; N, 3.85

Example 108 S-[6-Oxo-1-(4-phenoxybenzyl)-3-piperidinyl]ethanethioate

[1039] 179 mg (0.77 mmol) of5-{[tert-butyl(dimethyl)silyl]oxy}-2-piperidinone synthesized by amethod known in a literature (Arch. Pharm. (Weinheim), 316, pp719-723,1983), 34 mg (0.86 mmol) of 60% sodium hydride and 149 μl (0.82 mmol) of4-phenoxybenzyl chloride were stirred in 2 ml of THF at room temperaturefor 16 hours. The reaction mixture was concentrated under reducedpressure, treated with ethyl acetate, washed twice with water and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thereaction mixture was concentrated under reduced pressure to obtain5-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-phenoxybenzyl)-2-piperidinonewhich was then dissolved in 1 ml of THF, treated with 1.74 ml (1.74mmol) of a 1M solution of tetrabutylammonium fluoride in THF and stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent:methanol:ethyl acetate (1:9)) (yield: 83%in 2 steps) to obtain 187 mg (0.628 mmol) of5-hydroxy-1-(4-phenoxybenzyl)-2-piperidinone, which was stirred togetherwith 131 μl (0.94 mmol) of triethylamine and 73 μl (0.94 mmol) ofmethanesulfonyl chloride in 2 ml of chloroform at room temperature for15 minutes. The reaction mixture was concentrated under reducedpressure, treated with ethyl acetate, washed twice with water and thenwith saturated brine, and dried over anhydrous sodium sulfate to obtain(yield: 87%) 205 mg (0.55 mmol) of6-oxo-1-(4-phenoxybenzyl)-3-piperidinyl methanesulfonate which was thendissolved in 2 ml of DMF, treated with 106 mg (0.93 mmol) of potassiumthioacetate, and stirred at 70° C. for 12 hours. The reaction mixturewas treated with ethylacetate, washed 5 times with water and then withsaturated brine, and dried over anhydrous sodium sulfate. The reactionmixture was concentrated under reduced pressure and purified bypreparative thin layer chromatography (eluent:n-hexane:ethyl acetate(2:1)) to obtain 97 mg (yield: 50%) of the title compound as a paleyellow oil.

[1040] Elemental analysis (%): C₂₀H₂₁NO₃S

[1041] Calcd.: C, 67.58; H, 5.95; N, 3.94

[1042] Found: C, 67.33; H, 5.90; N, 3.80

Example 109 1-(4-Phenoxybenzyl)-5-sulfanyl-2-piperidinone

[1043] 20 mg (0.056 mmol) ofS-[6-oxo-1-(4-phenoxybenzyl)-3-piperidinyl)ethanethioate obtained inExample 108 was dissolved in 0.2 ml of ethanol, and 80 μl (1.13 mmol) ofacetyl chloride was added slowly. Thereafter, the mixture was stirred at50° C. for 1 hour, concentrated under reduced pressure, dissolved inethyl acetate, washed with saturated brine and dried over anhydroussodium sulfate. The reaction mixture was concentrated under reducedpressure and purified by preparative thin layer chromatography(eluent:n-hexane:ethyl acetate (2:3)) to obtain 14 mg (yield: 78%) ofthe title compound as a colorless oil.

[1044]¹H-NMR (300 MHz, CDCl3)

[1045] δ: 7.36-6.95 (9H, m), 4.59 (1H, d, J=14.6 Hz), 4.50 (1H, d,J=14.6 Hz), 3.51-3.43 (1H, m), 3.25-3.13 (2H, m), 2.71-2.45 (2H, m),2.25-2.16 (1H, m), 1.90-1.77 (1H, m), 1.62-1.59 (1H, m)

Example 110 S-[2-Oxo-1-(4-phenoxybenzyl)-4-piperidinyl]ethanethioate

[1046] Using alanine ethyl ester instead of glycine ethyl ester and by amethod similar to that in Example 15,S-[2-oxo-1-(4-phenoxybenzyl)-4-piperidinyl]ethanethioate was obtained.

[1047]¹H—NMR (200 MHz, CDCl₃)

[1048] d: 7.40-6.90 (9H, m), 4.62 (1H, d, J=14.7 Hz), 4.52 (1H, d,J=14.5 Hz), 3.92-3.78 (1H, m), 3.32 (1H, d, J=5.2 Hz), 3.29 (1H, d,J=5.3 Hz), 2.87 (1H, dd, J=5.7, 16.0 Hz), 2.50 (1H, dd, J=9.1, 18.0 Hz),2.33 (3H, s), 2.25-2.05 (1H, m), 1.95-1.76 (1H, m)

Example 111 1-(4-Phenoxybenzyl)-4-sulfanyl-2-piperidinone

[1049] From 20 mg (0.054 mmol) ofS-[2-oxo-1-(4-phenoxybenzyl)-4-piperidinyl]ethanethioate obtained inExample 110 and by a method similar to that in Example 184, 14 mg(yield: 82.6%) of 1-(4-phenoxybenzyl)-4-sulfanyl-2-piperidinone wasobtained as a colorless oil.

[1050]¹H-NMR (200 MHz, CDCl₃)

[1051] d: 7.40-6.90 (1H, m), 4.66 (1H, d, J=14.4 Hz), 4.48 (1H, d,J=14.6 Hz), 3.45-3.20 (3H, m), 2.92 (1H, dd, J=5.3, 18.0 Hz), 2.48 (1H,dd, J=9.1, 18.0 Hz), 2.25-2.10 (1H, m), 1.90-1.70 (1H, m), 1.67 (1H, d,J=6.5 Hz)

Example 112 4-Acetylthio-1-[4-(2′-fluorophenoxy)benzyl]pyrrolidin-2-one

[1052] By a method similar to that in Example 30 and starting from 1.67g (8.1 mmol) of 4-(2′-fluorophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 2-fluorophenol and 1.70 g (9.8 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 396 mg (yield: 17%) of4-acetylthio-1-[4-(2′-fluorophenoxy)benzyl]pyrrolidin-2-one was obtainedas a tan oil.

[1053] Elemental analysis (%): C₁₉H₈NO₃SF

[1054] Calcd.: C, 63.49; H, 5.05; N, 3.90; S, 8.92

[1055] Found: C, 63.24; H, 5.11; N, 3.85; S, 9.01

Example 113 4-Mercapto-1-[4-(2′-fluorophenoxy)benzyl]pyrrolidin-2-one

[1056] By a method similar to that in Example 31 and starting from 112mg (0.30 mmol) of4-acetylthio-1-[4-(2′-fluorophenoxy)benzyl]pyrrolidin-2-one obtained inExample 112, 97.0 mg (yield: 98%) of4-mercapto-1-[4-(2′-fluorophenoxy)benzyl]pyrrolidin-2-one was obtainedas a colorless oil.

[1057]¹H-NMR (300 MHz, CDCl₃)

[1058] δ: 7.20 (2H, d, J=8.5 Hz), 7.17-7.03 (4H, m), 6.94 (2H, d, J=8.5Hz), 4.47 (1H, d, J=14.7 Hz), 4.40 (1H, d, J=14.7 Hz), 3.64 (1H, dd,J=10.0, 7.2 Hz), 3.53 (1H, m), 3.16 (1H, dd, J=10.0, 5.0 Hz), 2.91 (1H,dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1, 6.1 Hz), 1.86 (1H, d, J=6.7Hz)

Example 114 4-Acetylthio-1-[4-(3′-fluorophenoxy)benzyl]pyrrolidin-2-one

[1059] By a method similar to that in Example 30 and starting from 1.73g (7.3 mmol) of 4-(3′-fluorophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 3-fluorophenol and 1.90 g (11 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 664 mg (yield: 25%) of4-acetylthio-1-[4-(3′-fluorophenoxy)benzyl]pyrrolidin-2-one was obtainedas a tan oil.

[1060] Elemental analysis (%): C₁₉H₁₈NO₃SF

[1061] Calcd.: C, 63.49; H, 5.05; N, 3.90; S, 8.92

[1062] Found: C, 63.19; H, 5.08; N, 3.79; S, 9.00

Example 115 4-Mercapto-1-[4-(3′-fluorophenoxy)benzyl]pyrrolidin-2-one

[1063] By a method similar to that in Example 31 and starting from 205mg (0.60 mmol) of4-acetylthio-1-[4-(3′-fluorophenoxy)benzyl]pyrrolidin-2-one obtained inExample 112, 143 mg (yield: 75%) of4-mercapto-1-[4-(3′-fluorophenoxy)benzyl]pyrrolidin-2-one was obtainedas a colorless oil.

[1064]¹H-NMR (300 MHz, CDCl₃)

[1065] δ: 7.28 (1H, m), 7.24 (2H, d, J=8.5 Hz), 7.00 (2H, d, J=8.5 Hz),6.79 (2H, ddd, J=11.4, 8.3, 2.5 Hz), 6.69 (1H, ddd, J=10.2, 2.3, 2.3Hz), 4.49 (1H, d, J=14.8 Hz), 4.42 (1H, d, J=14.8 Hz), 3.67 (1H, dd,J=10.1, 7.2 Hz), 3.55 (1H, m), 3.18 (1H, dd, J=10.1, 5.0 Hz), 2.92 (1H,dd, J=17.1, 8.1 Hz), 2.43 (1H, dd, J=17.1, 6.1 Hz), 1.88 (1H, d, J=6.7Hz)

Example 116(S)-4-Acethylthio-1-[4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one

[1066] 4-Acetylthio-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-onesynthesized in Example 30 was resolved by HPLC using a chiral column(DAICEL, CHIRALCEL OD 20×250 mm) (mobile phase=hexane:ethanol (90:10),flow rate=10 ml/min, Detection at 254 nm) to obtain(S)-4-acetylthio-1-[4-(4′-fluorophenoxy)benzyl]pyrrolidin-2-one.

[1067]¹H-NMR (300 MHz, CDCl₃)

[1068] δ: 7.18 (2H, d, J=8.5 Hz), 7.04 (2H, dd, J=9.3, 8.0 Hz), 6.97(2H, dd, J=9.3, 4.7 Hz), 6.92 (2H, d, J=8.5 Hz), 4.45 (1H, d, J=15.2Hz), 4.39 (1H, d, J=15.2 Hz), 4.05 (1H, m), 3.75 (1H, dd, J=10.6, 7.6Hz), 3.17 (1H, dd, J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.42(1H, dd, J=17.4, 6.1 Hz), 2.32 (3H, s)

Example 117(R)-4-Acethylthio-1-[4-(4′-fluorophenoxy)benzyl]pyrrolidin-2-one

[1069] By a method similar to that in Example 116,4-acetylthio-1-(4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one synthesizedin Example 30 was resolved by HPLC using a chiral column to obtain(R)-4-acetylthio-1-[4-(4′-fluorophenoxy)benzyl)pyrrolidin-2-one.

[1070]¹H-NMR (300 MHz, CDCl₃)

[1071] δ: 7.18 (2H, d, J=8.5 Hz), 7.04 (2H, dd, J=9.3, 8.0 Hz), 6.97(2H, dd, J=9.3, 4.7 Hz), 6.92 (2H, d, J=8.5 Hz), 4.45 (1H, d, J=15.2Hz), 4.39 (1H, d, J=15.2 Hz), 4.05 (1H, m), 3.75 (1H, dd, J=10.6, 7.6Hz), 3.17 (1H, dd, J=10.6, 5.0 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.42(1H, dd, J=17.4, 6.2 Hz), 2.32 (3H, s)

Example 118(R)-4-Mercapto-1-[4-(4′-fluorophenoxy)benzyl]pyrrolidin-2-one.

[1072] By a method similar to that in Example 31 and starting from(R)-4-acethylthio-1-[4-(4′-fluorophenoxy)benzyl]pyrrolidin-2-oneobtained in Example 117,(R)-4-mercapto-1-[4-(4′-fluorophenoxy)benzyl]pyrrolidin-2-one wasobtained.

[1073]¹H-NMR (300 MHz, CDCl₃)

[1074] δ: 7.22-6.91 (8H, m), 4.47 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 3.64 (1H, dd, J=10.0, 7.2 Hz), 3.59-3.48 (1H, m), 3.16 (1H,dd, J=10.0, 5.0 Hz), 2.91 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd,J=17.0, 6.1 Hz), 1.86 (1H, d, J=6.7 Hz)

Example 1194-Acetylthio-1-[4-(2′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one

[1075] By a method similar to that in Example 30 and starting from 1.83g (7.2 mmol) of 4-(2′,4′-difluorophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 2,4-difluorophenol and 1.50 g (8.6 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 288 mg (yield: 10%) of4-acetylthio-1-[4-(2′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one wasobtained as a white powder.

[1076] Elemental analysis (%): C₁₉H₁₇NO₃SF₂

[1077] Calcd.: C, 60.47; H, 4.54; N, 3.71; S, 8.50

[1078] Found: C, 60.69; H, 4.64; N, 3.81; S, 8.49

Example 1204-Mercapto-1-[4-(2′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one

[1079] By a method similar to that in Example 31 and starting from 10 mg(0.26 mmol) of4-acethylthio-1-[4-(2′,4′-difluorophenoxy)benzyl]pyrrolidin-2-oneobtained in Example 119, 60.0 mg (yield: 69%) of4-mercapto-1-[4-(2′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one wasobtained as a white powder.

[1080]¹H-NMR (300 MHz, CDCl₃)

[1081] δ: 7.19 (2H, d, J=8.5 Hz), 7.06 (1H, ddd, J=14.5, 9.0, 5.5 Hz),7.00-6.88 (2H, m), 6.89 (2H, d, J=8.5 Hz), 4.46 (1H, d, J=14.7 Hz), 4.38(1H, d, J=14.7 Hz), 3.64 (1H, dd, J=10.0, 7.2 Hz), 3.53 (1H, m), 3.15(1H, dd, J=10.0, 5.0 Hz), 2.90 (1H, dd, J=17.1, 8.1 Hz), 2.41 (1H, dd,J=17.1, 6.1 Hz), 1.85 (1H, d, J=6.7 Hz)

Example 1214-Acetylthio-1-[4-(3′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one

[1082] By a method similar to that in Example 30 and starting from 1.90g (7.5 mmol) of 4-(3′,4′-difluorophenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 3,4-difluorophenol and 1.60 g (9.0 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 506 mg (yield: 19%) of4-acetylthio-1-[4-(3′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one wasobtained as a pale tan powder.

[1083] Elemental analysis (%): C₁₉H₁₇NO₃SF₂

[1084] Calcd.: C, 60.47; H, 4.54; N, 3.71; S, 8.50

[1085] Found: C, 60.45; H, 4.51; N, 3.78; S, 8.48

Example 1224-Mercapto-1-[4-(3′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one

[1086] By a method similar to that in Example 31 and starting from 100mg (0.26 mmol) of4-acethylthio-1-[4-(3′,4′-difluorophenoxy)benzyl]pyrrolidin-2-oneobtained in

Example 121 55.0 mg (yield: 63%) of4-mercapto-1-[4-(3′,4′-difluorophenoxy)benzyl]pyrrolidin-2-one wasobtained as a white powder.

[1087]¹H-NMR (300 MHz, CDCl₃)

[1088] δ: 7.24 (2H, d, J=8.5 Hz), 7.12 (1H, dd, J=18.8, 9.1 Hz), 6.96(2H, d, J=8.5 Hz), 6.83 (1H, ddd, J=11.2, 6.6, 2.9 Hz), 6.72 (1H, m),4.49 (1H, d, J=14.8 Hz), 4.40 (1H, d, J=14.8 Hz), 3.67 (1H, dd, J=10.0,7.2 Hz), 3.55 (1H, m), 3.17 (1H, dd, J=10.0, 5.0 Hz), 2.92 (1H, dd,J=17.1, 8.1 Hz), 2.43 (1H, dd, J=17.1, 6.1 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 123(R)-4-Acethylthio-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one

[1089] (1) 5.00 g (24 mmol) of 4-(4′-methylphenoxy)benzaldehyde preparedfrom 4-fluorobenzaldehyde and 4-cresol similarly to Example 30 wasdissolved in 60 ml of ethanol and 30 ml of water, treated with 3.90 g(47 mmol) of sodium acetate and 2.10 g (31 mmol) of hydroxylammoniumchloride, and heated under reflux for 2 hours. The reaction mixture wasconcentrated under reduced pressure, treated with water and extractedtwice with ethyl acetate, and the organic layer obtained was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Themixture was concentrated under reduced pressure, and the residue wassolidified with hexane-ethyl acetate. The powder thus obtained wasdissolved in 100 ml of methanol, and 250 mg of 10% Pd/C was added, andthe mixture was stirred at room temperature under hydrogen atmosphere.The reaction mixture was filtered, concentrated under reduced pressure,treated with water and extracted twice with ethyl acetate, and theorganic layer obtained was washed with saturated sodium bicarbonate andsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, a 4N solution of hydrochloric acid in ethyl acetate wasadded to obtain 4.50 g (yield: 76%) of 4-(4′-methylphenoxy)benzylaminehydrochloride as a white powder.

[1090]¹H-NMR (300 MHz, CD₃OD)

[1091] δ: 8.23 (2H, brs), 7.46 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.3Hz), 7.00 (2H, d, J=8.6 Hz), 6.91 (2H, d, J=8.3 Hz), 4.11 (0.5H, brs),3.99 (1.5H, brs), 2.33 (3H, s),

[1092] (2) 4.50 g (18 mmol) of 4-(4′-methylphenoxy)benzylaminehydrochloride was dissolved in a solvent mixture of 25 ml oftetrahydrofuran and 50 ml of acetonitrile, treated with 2.8 ml (20 mmol)of triethylamine, and stirred at room temperature for 40 minutes. To4.00 g (25 mmol) of (S)-O-acetylmalic anhydride (TOKYO KASEI) was added,and the mixture was stirred at room temperature for 4.5 hours. Thereaction mixture was concentrated under reduced pressure, dissolved in50 ml of acetyl chloride, and heated under reflux for 3 hours. Themixture was concentrated under reduced pressure, treated with ethylacetate, washed with saturated sodium bicarbonate and saturated brine,and dried over anhydrous sodium sulfate. The mixture was concentratedunder reduced pressure, and the residue was subjected to columnchromatography on silica gel eluting with hexane:ethyl acetate(80:20-75:25) to obtain 3.80 g (yield: 60%) of(S)-3-acetoxy-1-[4-(4′-methylphenoxy)benzyl]pyrrolidine-2,5-dione as ayellow oil.

[1093]¹H-NMR (300 MHz, CDCl₃)

[1094] δ: 7.34 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.2 Hz), 6.91 (2H, d,J=8.6 Hz), 6.90 (2H, d, J=8.2 Hz), 5.45 (1H, dd, J=8.7, 4.8 Hz), 4.68(1H, d, J=13.2 Hz), 4.63 (1H, d, J=13.2 Hz), 3.16 (1H, dd, J=18.3, 8.7Hz), 2.67 (1H, dd, J=18.3, 4.8 Hz), 2.33 (3H, s), 2.16 (31H, s)

[1095] (3) 3.60 g (10 mmol) of(S)-3-acetoxy-1-[4-(4′-methylphenoxy)benzyl]pyrrolidine-2,5-dione wasdissolved in a solvent mixture of 40 ml of tetrahydrofuran and 20 ml ofethanol, and stirred at −18 to −13° C. When the temperature became thelowest, 386 mg (10 mmol) of sodium borohydride was added, and themixture was stirred at −18 to −13° C. for 8 hours. After the reactionand when the temperature became the lowest, saturated sodium bicarbonateand saturated brine were added, and the mixture was extracted threetimes with ethyl acetate, and the organic layer obtained was washed withsaturated brine and dried over anhydrous sodium sulfate. The mixture wasconcentrated under reduced pressure, and the residue was treated with 50ml of trifluoroacetic acid and 1.6 ml (10 mmol) of triethylsilane, andstirred at room temperature for 35 minutes. 2.8 ml (20 mmol) oftriethylamine was added, and the mixture was stirred at room temperaturefor 40 minutes. The residue obtained by concentrating under reducedpressure after completion of the reaction was added to a solution of 30ml of ethanol with 15 ml (0.20 mol) of acetyl chloride, and heated at50° C. with stirring for 2 hours. The mixture was concentrated underreduced pressure, and the residue was subjected to column chromatographyon silica gel eluting with hexane:acetone (50:50) to obtain 2.20 g(yield: 73%) of(S)-4-hydroxy-1-[4-(4′-methylphenoxy)benzyl)pyrrolidin-2-one as a whitepowder.

[1096]¹H-NMR (300 MHz, CDCl₃)

[1097] δ: 7.18 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.3 Hz), 6.93 (2H, d,J=8.5 Hz), 6.90 (2H, d, J=8.3 Hz), 4.49 (1H, m), 4.44 (2H, s), 3.52 (1H,dd, J=10.9, 5.6 Hz), 3.20 (1H, dd, J=10.9, 1.9 Hz), 2.74 (1H, dd,J=17.4, 6.6 Hz), 2.44 (1H, dd, J=17.4, 2.3 Hz), 2.35 (1H, brs), 2.33(3H, s)

[1098] (4) 2.00 g (6.7 mmol) of(S)-4-hydroxy-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one wasdissolved in 15 ml of chloroform, and 0.73 ml (9.4 mmol) ofmethanesulfonyl chloride was added and the mixture was stirred withcooling on ice. To this mixture, a solution of 1.3 ml (9.4 mmol) oftriethylamine in 5 ml of chloroform was added dropwise over a period of10 minutes, and the mixture was stirred further for 3 hours with coolingon ice. The mixture was concentrated under reduced pressure, treatedwith ethyl acetate, washed three times with water and then withsaturated brine, and dried over anhydrous sodium sulfate. The mixturewas concentrated under reduced pressure, and the residue was washed withethyl acetate-hexane to obtain 2.40 g (yield: 95%) of(S)-4-methanesulfonyloxy-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-oneas a white powder.

[1099]¹H-NMR (300 MHz, CDCl₃)

[1100] δ: 7.18 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.6 Hz), 6.94 (2H, d,J=8.3 Hz), 6.91 (2H, d, J=8.3 Hz), 5.29 (1H, m), 4.49 (1H, d, J=15.0Hz), 4.42 (1H, d, J=15.0 Hz), 3.66 (1H, dd, J=12.0, 5.7 Hz), 3.52 (1H,dd, J=12.0, 2.0 Hz), 3.02 (3H, s), 2.87 (1H, dd, J=17.9, 6.8 Hz), 2.71(1H, dd, J=17.9, 2.5 Hz), 2.34 (3H, s)

[1101] (5) 1.30 g (8.30 mmol) of cesium carbonate was dispersed in 10 mlof N,N-dimethylformamide, and 2.1 ml (30 mmol) of thioacetic acid wasadded, and the mixture was stirred at room temperature for severalminutes. Thereafter, the mixture was deaerated under reduced pressure toobtain a solution of cesium thioacetate. 2.20 g (5.9 mmol) of(S)-4-methanesulfonyloxy-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-onewas dissolved in 10 ml of N,N-dimethylformamide to which the solution ofcesium thioacetate prepared above was added, and the mixture was furtherdeaerated under reduced pressure. This solution was stirred undernitrogen atmosphere at room temperature for 61 hours. This reactionmixture was treated with water and extracted three times with ethylacetate, and the organic layer obtained was washed three times withwater and then with saturated brine, and dried over anhydrous sodiumsulfate. The mixture was concentrated under reduced pressure, and theresidue was subjected to column chromatography on silica gel elutingwith hexane:ethyl acetate (80:20-70:30) and the effluent was treatedwith an activated charcoal to obtain 1.70 g (yield: 81%) of(R)-4-acethylthio-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one as apale red oil.

[1102]¹H-NMR (300 MHz, CDCl₃)

[1103] δ: 7.17 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.3 Hz), 6.93 (2H, d,J=8.4 Hz), 6.91 (2H, d, J=8.3 Hz), 4.45 (1H, d, J=14.7 Hz), 4.38 (1H, d,J=14.7 Hz), 4.05 (1H, m), 3.75 (1H, dd, J=10.7, 7.6 Hz), 3.16 (1H, dd,J=10.7, 5.0 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.41 (1H, dd, J=17.4,6.0 Hz), 2.34 (3H, s), 2.32 (3H, s)

Example 124(R)-4-Acethylthio-1-[4-(4′-ethylphenoxy)benzyl]pyrrolidin-2-one

[1104] By a method similar to that in Example 123 and starting from4-(4′-methylphenoxy)benzylamine, which was prepared from4-fluorobenzaldehyde and 4-ethylphenol, and (S)-O-acetylmalic anhydride,(R)-4-acethylthio-1-[4-(4′-ethylphenoxy)benzyl]pyrrolidin-2-one wasobtained as a pale red oil.

[1105]¹H-NMR (300 MHz, CDCl₃)

[1106] δ: 7.17 (4H, d, J=8.5 Hz), 6.92 (2H, d, J=8.6 Hz), 6.92 (2H, d,J=8.5 Hz), 4.46 (1H, d, J=14.7 Hz), 4.39 (1H, d, J=14.7 Hz), 4.05 (1H,m), 3.75 (1H, dd, J=10.6, 7.5 Hz), 3.16 (1H, dd, J=10.6, 5.0 Hz), 2.91(1H, dd, J=17.4, 8.9 Hz), 2.63 (2H q, J=7.6 Hz), 2.42 (1H, dd, J=17.4,6.0 Hz), 2.31 (3H, s), 1.24 (3H, t, J=7.6 Hz)

Example 125(R)-4-Acethylthio-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one

[1107] (1) Starting from 30.0 g (233 mmol) of 4-chlorophenol, 28.9 g(233 mmol) of 4-fluorobenzaldehyde and 32.2 g (233 mmol) of potassiumcarbonate, 51.8 g (yield: 96%) of 4-(4-chlorophenoxy)benzaldehyde wasobtained as pale yellow prisms.

[1108]¹H-NMR (300 MHz, CDCl₃)

[1109] δ: 9.93 (1H, s), 7.86 (2H, d, J=8.7 Hz), 7.38 (2H, d, J=9.0 Hz),7.04 (4H, m)

[1110] (2) Starting from 46.5 g (200 mmol) of4-(4-chlorophenoxy)benzaldehyde, 17.4 g (250 mmol) of hydroxylaminehydrochloride and 25.2 g (300 mmol) of sodium hydrogen carbonate, 47.9 g(yield: 97%) of 4-(4-chlorophenoxy)benzaldehyde oxime was obtained as awhite powder.

[1111]¹H-NMR (300 MHz, CDCl₃)

[1112] δ8.11 (1H, s), 7.55 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=9.1 Hz),6.98 (4H, m)

[1113] (3) 800 ml of diethyl ether was treated with 22.8 g (600 mmol) oflithium aluminum hydride, and a solution of 46.9 g (189 mmol) of4-(4-chlorophenoxy)benzaldehyde oxime in 200 ml of diethyl ether wasadded dropwise over a period of 1 hour with stirring. The reactionmixture was treated with water with cooling on ice and filtered throughCelite, and the precipitate was washed with ethyl acetate, and theorganic phase was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The mixture was concentrated under reducedpressure, dissolved in ethyl acetate, treated with 80 ml of 4Nhydrochloric acid/ethyl acetate and then allowed to stand. Theprecipitate was collected by filtration, washed several times withdiethyl ether and dried to obtain 43.7 g (yield: 86%) of4-(4-chlorophenoxy)benzylamine hydrochloride as a white powder.

[1114]¹H-NMR (300 MHz, DMSO-d₆)

[1115] δ: 8.42 (2H, brs), 7.53 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.9Hz), 7.08 (2H, d, J=8.3 Hz), 7.02 (2H, d, J=8.9 Hz), 4.00 (2H, s)

[1116] (4) Similarly to Example 123 and starting from 30.0 g (111 mmol)of 4-(4-chlorophenoxy)benzylamine hydrochloride, 15.5 ml (111 mmol) oftriethylamine and 20.2 g (128 mmol) of (S)—O-acetylmalic anhydride, 39.4g (yield: 95%) of (S)-3-acetoxy-1-[4-(4-chlorophenoxy)benzyl]succinimidewas obtained as a colorless oil.

[1117]¹H-NMR (300 MHz, CDCl₃)

[1118] δ: 7.36 (2H, d, J=8.7 Hz), 7.28 (2H, d, J=9.0 Hz), 6.93 (4H, m),5.45 (1H, dd, J=8.9, 4.9 Hz), 4.70 (1H, d, J=14.3 Hz), 4.64 (1H, d,J=14.3 Hz), 3.17 (1H, dd, J=18.5, 8.9 Hz), 2.68 (1H, dd, J=18.5, 4.9Hz), 2.16 (3H, s)

[1119] (5) 39.0 g (104 mmol) of(S)-3-acetoxy-1-[4-(4-chlorophenoxy)benzyl]succinimide, 3.93 g (104mmol) of sodium borohydride and 16.6 ml (104 mmol) of triethylsilanewere subjected respectively to a reduction, followed by hydrolysis toobtain 14.8 g (yield: 45%) of(S)-4-hydroxy-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one as a paleyellow oil.

[1120] Elemental analysis (%): C₁₇H₁₆NO₃Cl*0.3H₂O

[1121] Calcd.: C, 63.18; H, 5.18; N, 4.33

[1122] Found: C, 63.13; H, 5.06; N, 4.34

[1123] (6) Starting from 14.5 g (45.6 mmol) of(S)-4-hydroxy-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one, 4.94 ml(63.8 mmol) of methanesulfonyl chloride and 8.90 ml (63.8 mmol) oftriethylamine, 14.6 g (yield: 81%) of(S)-4-methanesulfonyloxy-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-onewas obtained as a white powder.

[1124] Elemental analysis (%): C₁₉H₁₈NO₅SC·0.2H₂O Calcd.: C, 54.12;H,4.64;N, 3.51 Found: C, 54.09;H, 4.59;N, 3.43 (7) Starting from 14.0 g(35.4 mmol) of(S)-4-methanesulfonyloxy-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one,12.7 ml (177 mmol) of thioacetic acid and 8.07 g (24.8 mmol) of cesiumcarbonate, 11.7 g (yield: 88%) of(R)-4-acetylthio-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one wasobtained as a tan oil. Elemental analysis (%): C₁₉H₁₈NO₃SC10.25H₂OCalcd.: C, 59.99;H, 4.90;N, 3.68 Found: C, 59.96;H, 4.78;N, 3.67 Example126 (R)-4-Mercapto-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one To 23ml of ethanol with cooling on ice, 8.55 ml (120 mmol) of acetyl chloridewas added dropwise over a period of 30 minutes with stirring. In thissolution, 2.26 g (6.01 mmol) of(R)-4-acetylthio-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one obtainedin Example 125 was dissolved and heated at 50° C. for 1.5 hours withstirring. The reaction mixture was concentrated under reduced pressure,treated with ethyl acetate, washed with water and saturated brine anddried over anhydrous sodium sulfate. The mixture was concentrated underreduced pressure, and the residue was subjected to column chromatographyon silica gel, and the fraction eluted with hexane:ethyl acetate (40:60)was concentrated under reduced pressure to obtain 1.29 g (yield: 64%) of(R)-4-mercapto-1-[4-(4-chlorophenoxy)benzyl]pyrrolidin-2-one as a palered oil.

[1125] Elemental analysis (%): C₁₇H₁₆NO₂SCl·0.2H₂O

[1126] Calcd.: C, 60.51; H, 4.90; N, 4.15

[1127] Found: C, 60.41; H, 4.96;N, 4.12 Example 127(R)-4-Acetylthio-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one

[1128] By a method similar to that in Example 30 and starting from 1.97g (8.9 mmol) of 4-(4′-methylphenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 4-cresol and 1.50 g (8.9 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 397 mg (yield: 12%) of4-acetylthio-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one was obtainedas a white powder.

[1129] Elemental analysis (%): C₂₀H₂₁NO₃S

[1130] Calcd.: C, 67.58; H, 5.95;N, 3.94;S, 9.02

[1131] Found: C, 67.53; H, 5.94;N, 4.15;S, 9.05

Example 128 4-Mercapto-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one

[1132] By a method similar to that in Example 31 and starting from 103mg (0.30 mmol) of4-acetylthio-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one obtained inExample 127, 87 mg (yield: 96%) of4-mercapto-1-[4-(4′-methylphenoxy)benzyl]pyrrolidin-2-one was obtainedas a colorless oil.

[1133]¹H-NMR (300 MHz, CDCl₃)

[1134] δ: 7.18 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.4 Hz), 6.93 (2H, d,J=8.5 Hz), 6.91 (2H, d, J=8.4 Hz), 4.46 (1H, d, J=14.7 Hz), 4.39 (1H, d,J=14.7 Hz), 3.64 (1H, dd, J=10.0, 7.3 Hz), 3.53 (1H, m), 3.16 (1H, dd,J=10.0, 5.1 Hz), 2.91 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1,6.2 Hz), 2.34 (3H, s) 1.86 (1H, d, J=6.7 Hz)

Example 1294-Acetylthio-1-[4-(4′-(trifluoromethyl)phenoxy)benzyl]pyrrolidin-2-one

[1135] By a method similar to that in Example 30 and starting from 382mg (1.3 mmol) of 4-(4′-(trifluoromethyl)phenoxy)benzyl chloride preparedfrom 4-fluorobenzaldehyde and 4-(trifluoromethyl)phenol and 338 mg (2.0mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 95.0 mg (yield: 18%) of4-acetylthio-1-{4-[4′-(trifluoromethyl)phenoxy]benzyl}pyrrolidin-2-onewas obtained as a colorless oil.

[1136]¹H-NMR (300 MHz, CDCl₃)

[1137] δ 7.58 (2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.5 Hz), 7.05 (2H, d,J=8.7 Hz), 7.02 (2H, d, J=8.5 Hz), 4.49 (1H, d, J=15.0 Hz), 4.42 (1H, d,J=15.0 Hz), 4.07 (1H, m), 3.78 (1H, dd, J=10.6, 7.5 Hz), 3.19 (1H, dd,J=10.6, 5.0 Hz), 2.93 (1H, dd, J=17.5, 9.0 Hz), 2.44 (1H, dd, J=17.4,6.0 Hz), 2.33 (3H, s)

Example 1304-Mercapto-1-{4-[4′-(trifluoromethyl)phenoxy]benzyl}pyrrolidin-2-one

[1138] By a method similar to that in Example 31 and starting from 58.0mg (0.14 mmol) of4-acetylthio-1-{4-[4′-(trifluoromethyl)phenoxy]benzyl}pyrrolidin-2-oneobtained in Example 129, 46.0 mg (yield: 89%) of4-mercapto-1-{4-[4′-(trifluoromethyl)phenoxy]benzyl}pyrrolidin-2-one wasobtained as a colorless oil.

[1139]¹H-NMR (300 MHz, CDCl₃)

[1140] δ: 7.58 (2H, d, J=8.7 Hz), 7.27 (2H, d, J=8.7 Hz), 7.04 (2H, d,J=8.4 Hz), 7.02 (2H, d, J=8.4 Hz), 4.52 (1H, d, J=14.8 Hz), 4.42 (1H, d,J=14.8 Hz), 3.68 (1H, dd, J=10.0, 7.2 Hz), 3.56 (1H, m), 3.19 (1H, dd,J=10.0, 5.0 Hz), 2.94 (1H, dd, J=17.1, 8.1 Hz), 2.43 (1H, dd, J=17.1,6.1 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 1314-Acetylthio-1-[4-(4′ethoxycarbonylphenoxy)benzyl]pyrrolidin-2-one

[1141] By a method similar to that in Example 30 and starting from ethyl4-(4′-chloromethylphenoxy)benzoate prepared from 4-fluorobenzaldehydeand ethyl 4-hydroxybenzoate and 4-trimethylsilyloxypyrrolidin-2-one,4-acetylthio-1-[4-(4′-ethoxycarbonylphenoxy)benzyl]pyrrolidin-2-one wasobtained as a colorless oil (yield: 17%).

[1142]¹H-NMR (300 MHz, CDCl₃)

[1143] δ: 8.02 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.6 Hz), 7.02 (2H, d,J=8.6 Hz), 6.98 (2H, d, J=8.8 Hz), 4.49 (1H, d, J=14.9 Hz), 4.42 (1H, d,J=14.9 Hz), 4.56 (2H, q, J=7.1 Hz), 4.07 (1H, m), 3.78 (1H, dd, J=10.6,7.5 Hz), 3.19 (1H, dd, J=10.6, 4.9 Hz), 2.93 (1H, dd, J=17.4, 8.9 Hz),2.44 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s), 1.39 (3H, t, J=7.1 Hz)

Example 1324-Mercapto-1-[4-(4′-ethoxycarbonylphenoxy)benzyl]pyrrolidin-2-one

[1144] By a method similar to that in Example 31 and starting from 108mg (0.26 mmol) of4-acetylthio-1-[4-(4′-ethoxycarbonylphenoxy)benzyl]pyrrolidin-2-oneobtained in Example 131, 100 mg of4-mercapto-1-[4-(4′-ethoxycarbonylphnoxy)benzyl]pyrrolidin-2-one wasobtained almost quantitatively as a pale yellow oil.

[1145]¹H-NMR (300 MHz, CDCl₃)

[1146] δ: 8.01 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.5 Hz), 7.02 (2H, d,J=8.5 Hz), 6.98 (2H, d, J=8.8 Hz), 4.51 (1H, d, J=14.8 Hz), 4.42 (1H, d,J=14.8 Hz), 4.36 (2H, q, J=7.1 Hz), 3.68 (1H, dd, J=10.1, 7.2 Hz), 3.56(1H, m), 3.19 (1H, dd, J=10.1, 5.0 Hz), 2.93 (1H, dd, J=17.1, 8.1 Hz),2.43 (1H, dd, J=17.1, 6.0 Hz), 1.88 (1H, d, J=6.7 Hz), 1.48 (3H, t,J=7.1 Hz)

Example 133 4-Acetylthio-1-[4-(4′-carboxyphenoxy)benzyl]pyrrolidin-2-one

[1147] (1) By a method similar to that in Example 30 and starting from6.20 g (18 mmol) of benzyl 4-(4′-chloromethylphenoxy)benzoate preparedfrom 4-fluorobenzaldehyde and benzyl 4-hydroxybenzoate and 3.00 g (18mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 471 mg (yield: 5%) of4-methanesulfonyloxy-1-[4-(4′-benzyloxycarbonylphenoxy)benzyl]pyrrolidin-2-onewas obtained as a tan oil.

[1148]¹H-NMR (300 MHz, CDCl₃)

[1149] δ: 8.05 (2H, d, J=8.8 Hz), 7.48-7.32 (5H, m), 7.25 (2H, d, J=8.5Hz), 7.03 (2H, d, J=8.5 Hz), 6.98 (2H, d, J=8.8 Hz), 5.35 (2H, s), 5.30(1H, m), 4.50 (2H, s), 3.69 (1H, dd, J=12.0, 5.6 Hz), 3.55 (1H, dd,J=12.0, 1.9 Hz), 3.03 (3H, s), 2.89 (1H, dd, J=17.9, 6.8 Hz), 2.72 (1H,dd, J=17.9, 2.4 Hz)

[1150] (2) 471 mg (1.1 mmol) of4-methanesulfonyloxy-1-[4-(4′-benzyloxycarbonylphenoxy)benzyl]pyrrolidin-2-onewas dissolved in 20 ml of tetrahydrofuran, 24.0 mg of 10% Pd/C wasadded, and the mixture was stirred under hydrogen atmosphere at roomtemperature for 2.5 hours. The reaction mixture was filtered andconcentrated under reduced pressure, and the residue was precipitatedfrom hexane-ethyl acetate to obtain 240 mg (yield: 59%) of4-methanesulfonyloxy-1-[4-(4′-carboxylphenoxy)benzyl]pyrrolidin-2-one asa white powder.

[1151]¹H-NMR (300 MHz, CDCl₃)

[1152] δ: 8.08 (2H, d, J=8.7 Hz), 7.27 (2H, d, J=8.6 Hz), 7.06 (2H, d,J=8.6 Hz), 7.01 (2H, d, J=8.7 Hz), 5.31 (1H, m), 4.51 (2H, s), 3.71 (1H,dd, J=12.0, 5.6 Hz), 3.57 (1H, dd, J=12.0, 2.0 Hz), 3.04 (3H, s), 2.91(1H, dd, J=18.0, 6.9 Hz), 2.74 (1H, dd, J=18.0, 2.2 Hz)

[1153] (3) 240 mg (0.59 mmol) of4-methanesulfonyloxy-1-[4-(4′-carboxylphenoxy)benzyl]pyrrolidin-2-onewas dissolved in 20 ml of ethanol, and 822 mg (3.0 mmol) of potassiumthioacetate was added, and the mixture was heated under reflux for 2hours. The reaction mixture was concentrated under reduced pressure,treated with 5% aqueous sodium hydrogen sulfate and extracted twice withethyl acetate, and the organic layer obtained was washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The mixturewas concentrated under reduced pressure, and the residue was subjectedto column chromatography on silica gel eluting with chloroform:methanol(98:1) and then again to column chromatography on silica gel elutingwith hexane:ethyl acetate (40:60) to obtain 103 mg (yield: 45%) of4-acetylthio-1-[4-(4′-carboxylphenoxy)benzyl]pyrrolidin-2-one as a paleyellow powder.

[1154]¹H-NMR (300 MHz, CDCl₃)

[1155] δ: 8.07 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.4 Hz), 7.04 (2H, d,J=8.4 Hz), 7.01 (2H, d, J=8.8 Hz), 4.51 (1H, d, J=14.8 Hz), 4.43 (1H, d,J=14.8 Hz), 4.07 (1H, m), 3.79 (1H, dd, J=10.6, 7.5 Hz), 3.20 (1H, dd,J=10.6, 5.0 Hz), 2.94 (1H, dd, J=17.4, 9.0 Hz), 2.44 (1H, dd, J=17.4,6.0 Hz), 2.33 (3H, s)

Example 1344-Acetylthio-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-one

[1156] (1) 310 mg (0.76 mmol) of4-methanesulfonyloxy-1-[4-(4′-carboxylphenoxy)benzyl]pyrrolidin-2-oneprepared by a method similar to that in Example 133 was dissolved in 5ml of thionyl chloride, and stirred at room temperature for 1.5 hours.The reaction mixture was concentrated under reduced: pressure, treatedwith 5 ml of tetrahydrofuran and 1 ml of conc. aqueous ammonia, andstirred at room temperature for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure, treated with dilute hydrochloricacid and extracted twice with ethyl acetate, and the organic layerobtained was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The reaction mixture was concentrated underreduced pressure, and the residue was precipitated from hexane-ethylacetate to obtain 147 mg (yield: 48%) of4-methanesulfonyloxy-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-oneas a white powder.

[1157]¹H-NMR (300 MHz, DMSO-d₆)

[1158] δ: 7.87 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz), 7.04 (2H, d,J=8.5 Hz), 6.98 (2H, d, J=8.5 Hz), 5.29 (1H, m), 4.53 (1H, brs), 4.41(2H, s), 3.97 (1H, brs), 3.69 (1H, dd, J=11.5, 5.4 Hz), 3.41 (1H, d,J=11.5 Hz), 3.30 (1H, m), 3.21 (3H, s), 2.91 (1H, dd, J=17.9, 6.9 Hz)

[1159] (2) 147 mg (0.36 mmol) of4-methanesulfonyloxy-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-onewas dissolved in 20 ml of ethanol, treated with 123 mg (1.1 mmol) ofpotassium thioacetate, and heated under reflux for 1.5 hours. Thereaction mixture was concentrated under reduced pressure, treated withwater and extracted twice with ethyl acetate, and the organic layerobtained was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The mixture was concentrated under reducedpressure, and the residue was subjected to column chromatography onsilica gel eluting with chloroform:methanol (98:2-95:5) to obtain 62.0mg (yield: 45%) of4-acethylthio-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-one as awhite powder.

[1160]¹H-NMR (300 MHz, CDCl₃)

[1161] δ: 7.80 (2H, d, J=8.7 Hz), 7.24 (2H, d, J=8.5 Hz), 7.01 (2H, d,J=8.7 Hz), 7.01 (2H, d, J=8.5 Hz), 5.90 (2H, brs), 4.49 (1H, d, J=14.9Hz), 4.42 (1H, d, J=14.9 Hz), 4.07 (1H, m), 3.78 (1H, dd, J=10.6, 7.5Hz), 3.20 (1H, dd, J=10.6, 4.9 Hz), 2.93 (1H, dd, J=17.4, 9.0 Hz), 2.43(1H, dd, J=17.4, 6.0 Hz), 2.33 (3H, s)

Example 1354-Mercapto-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-one

[1162] By a method similar to that in Example 31 and starting from 23.0mg (0.060 mmol) of4-acetylthio-1-[4-(4′-carboxamidephenoxy)benzyl]pyrrolidin-2-oneobtained in Example 134, 22.0 mg of4-mercapto-1-[4-(4′-aminocarbonylphenoxy)benzyl]pyrrolidin-2-one wasobtained almost quantitatively as a colorless oil.

[1163]¹H-NMR (300 MHz, CDCl₃)

[1164] δ: 7.79 (2H, d, J=8.7 Hz), 7.27 (2H, d, J=8.6 Hz), 7.02 (2H, d,J=8.6 Hz), 7.02 (2H, d, J=8.7 Hz), 5.90-5.60 (2H, brd), 4.51 (1H, d,J=14.8 Hz), 4.42 (1H, d, J=14.8 Hz), 3.68 (1H, dd, J=10.0, 7.3 Hz), 3.57(1H, m), 3.19 (1H, dd, J=10.0, 5.0 Hz), 2.93 (1H, dd, J=17.1, 8.1 Hz),2.43 (1H, dd, J=17.1, 6.0 Hz), 1.88 (1H, d, J=6.7 Hz)

Example 136 4-Acetylthio-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one

[1165] (1) 1.16 g (3.1 mmol) of4-methanesulfonyloxy-1-[4-(4′-methoxyphenoxy)benzyl]pyrrolidin-2-oneprepared by a method similar to that in Example 36 was dissolved in 25ml of chloroform, and treated with 4 ml of boron tribromide (3Mdichloromethane solution) and then stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure,treated with ethyl acetate, washed with water and saturated brine, anddried over anhydrous sodium sulfate. The mixture was concentrated underreduced pressure and the residue was subjected to column chromatographyon silica gel eluting with ethyl acetate to obtain 933 mg (yield: 80%)of 4-methanesulfonyloxy-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-oneas a gray powder.

[1166]¹H-NMR (300 MHz, CDCl₃)

[1167] δ: 7.15 (2H, d, J=8.5 Hz), 6.91 (2H, d, J=9.0 Hz), 6.88 (2H, d,J=8.5 Hz), 6.82 (2H, d, J=9.0 Hz), 5.35 (1H, s), 5.28 (1H, m), 4.49 (1H,d, J=14.7 Hz), 4.41 (1H, d, J=14.7 Hz), 3.66 (1H, dd, J=12.0, 5.6 Hz),3.52 (1H, dd, J=12.0, 1.8 Hz), 3.02 (3H, s), 2.88 (1H, dd, J=18.0, 6.8Hz), 2.72 (1H, dd, J=18.0, 2.4 Hz)

[1168] (2) 933 mg (2.5 mmol) of4-methanesulfonyloxy-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one wasdissolved in 50 ml of ethanol, treated with 1.40 g (13 mmol) ofpotassium thioacetate, and heated under reflux for 2 hours. The reactionmixture was concentrated under reduced pressure, treated with water andextracted twice with ethyl acetate, and the organic layer obtained waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate. The mixture was concentrated under reduced pressure, and theresidue was subjected to column chromatography on silica gel elutingwith hexane:ethyl acetate (50:50) and then again to columnchromatography on silica gel eluting with chloroform to obtain 434 mg(yield: 49%) of4-acetylthio-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one as acolorless oil.

[1169] Elemental analysis (%): C₁₉H₁₉NO₄S

[1170] Calcd.: C, 63.85; H, 5.36; N, 3.92; S, 8.97

[1171] Found: C, 63.66; H, 5.16; N, 4.05; S, 8.86

Example 137 4-Mercapto-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one

[1172] By a method similar to that in Example 31 and starting from 58.0mg (0.16 mmol) of4-acetylthio-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one obtained inExample 136, 35.0 mg (yield: 68%) of4-mercapto-1-[4-(4′-hydroxyphenoxy)benzyl]pyrrolidin-2-one was obtainedas a white powder.

[1173]¹H-NMR (300 MHz, CDCl₃)

[1174] δ: 8.42 (1H, s), 7.09 (2H, d, J=8.5 Hz), 6.81 (2H, d, J=8.5 Hz),6.79 (4H, d, J=4.7 Hz), 4.37 (1H, d, J=14.7 Hz), 4.31 (1H, d, J=14.7Hz), 3.58 (1H, dd, J=10.0, 7.2 Hz), 3.47 (1H, m), 3.09 (1H, dd, J=10.0,5.0 Hz), 2.84 (1H, dd, J=17.0, 8.1 Hz), 2.34 (1H, dd, J=17.0, 6.1 Hz),1.83 (1H, d, J=6.7 Hz)

Example 138 4-Acetylthio-1-[4-(4′-ethoxyphenoxy)benzyl]pyrrolidin-2-one

[1175] By a method similar to that in Example 30 and starting from 1.83g (7.0 mmol) of 4-(4′-ethoxyphenoxy)benzyl chloride prepared from4-fluorobenzaldehyde and 4-ethoxyphenol and 1.20 g (7.0 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 667 mg (yield: 25%) of4-acetylthio-1-{4-[4′-ethoxyphenoxy)benzyl]pyrrolidin-2-one was obtainedas a yellow oil.

[1176] Elemental analysis (%): C₂₁H₂₃NO₄S

[1177] Calcd.: C, 65.43; H, 6.01; N, 3.63;S, 8.32

[1178] Found: C, 65.61; H, 5.93; N, 3.75; S, 8.29

Example 139 4-Mercapto-1-[4-(4′-ethoxyphenoxy)benzyl]pyrrolidin-2-one

[1179] By a method similar to that in Example 31 and starting from 192mg (0.50 mmol) of4-acetylthio-1-[4-(4′-ethoxyphenoxy)benzyl]pyrrolidin-2-one obtained inExample 138, 128 mg (yield: 75%) of4-mercapto-1-[4-(4′-ethoxyphenoxy)benzyl]pyrrolidin-2-one was obtainedas a colorless oil.

[1180]¹H-NMR (300 MHz, CDCl₃)

[1181] δ: 7.17 (2H, d, J=8.6 Hz), 6.96 (2H, d, J=9.1 Hz), 6.89 (2H, d,J=8.6 Hz), 6.87 (2H, d, J=9.1 Hz), 4.45 (1H, d, J=14.7 Hz), 4.38 (1H, d,J=14.7 Hz), 4.02 (2H, q, J=7.0 Hz), 3.63 (1H, dd, J=10.0, 7.2 Hz), 3.52(1H, m), 3.15 (1H, dd, J=10.0, 5.1 Hz), 2.91 (1H, dd, J=17.0, 8.2 Hz),2.42 (1H, dd, J=17.0, 6.2 Hz), 1.86 (1H, d, J=6.8 Hz), 1.42 (3H, t,J=7.0 Hz)

Example 1404-Acetylthio-1-{4-[4′-(trifluoromethoxy)phenoxy]benzyl}pyrrolidin-2-one

[1182] By a method similar to that in Example 30 and starting from 1.85g (6.1 mmol) of 4-[4′-(trifluoromethoxy)phenoxy]benzyl chloride preparedfrom 4-fluorobenzaldehyde and 4-(trifluoromethoxy)phenol and 1.60 g (9.2mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 639 mg (yield: 25%) of4-acetylthio-1-{4-[4′-(trifluoromethoxy)phenoxy]benzyl}pyrrolidin-2-onewas obtained as a white powder.

[1183] Elemental analysis (%): C₂₀H₁₈NO₄SF₃

[1184] Calcd.: C, 56.46; H, 4.26; N, 3.29; S, 7.54

[1185] Found: C, 56.57; H, 4.26; N, 3.47; S, 7.51

Example 1414-Mercapto-1-{4-[4′-(trifluoromethoxy)phenoxy]benzyl}pyrrolidin-2-one

[1186] By a method similar to that in Example 31 and starting from 160mg (0.40 mmol) of4-acetylthio-1-{4-[4′-(trifluoromethoxy)phenoxy]benzyl}pyrrolidin-2-oneobtained in Example 140, 102 mg (yield: 71%) of4-mercapto-1-{4-[4′-(trifluoromethoxy)phenoxy]benzyl}pyrrolidin-2-onewas obtained as a colorless oil.

[1187]¹H-NMR (300 MHz, CDCl₃)

[1188] δ: 7.23 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=8.5 Hz), 7.00 (2H, d,J=8.5 Hz), 6.97 (2H, d, J=8.5 Hz), 4.49 (1H, d, J=1.4.8 Hz), 4.40 (1H,d, J=1-4.8 Hz), 3.66 (1H, dd, J=10.0, 7.2 Hz), 3.55 (1H, m), 3.17 (1H,dd, J=10.0, 5.0 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.43 (1H, dd,J=17.1, 6.1 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 142 4-Acetylthio-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one

[1189] By a method similar to that in Example 30 and starting from4-(4′-nitrophenoxy)benzyl chloride prepared from 4-hydroxybenzaldehydeand p-dinitrobenzene and 4-trimethylsilyloxypyrrolidin-2-one,4-acetylthio-1-(4-[4′-nitrophenoxy)benzyl]pyrrolidin-2-one was obtainedas a yellow oil (yield: 8%).

[1190]¹H-NMR (300 MHz, CDCl₃)

[1191] δ: 8.21 (2H, d, J=9.2 Hz), 7.30 (2H, d, J=8.5 Hz), 7.06 (2H, d,J=8.5 Hz), 7.02 (2H, d, J=9.2 Hz), 4.48 (2H, s), 4.08 (1H, m), 3.80 (1H,dd, J=10.6, 7.6 Hz), 3.21 (1H, dd, J=10.6, 5.0 Hz), 2.93 (1H, dd,J=17.4, 9.0 Hz), 2.45 (1H, dd, J=17.4, 6.1 Hz), 2.34 (3H, s)

Example 143 4-Mercapto-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one

[1192] By a method similar to that in Example 31 and starting from 52.0mg (0.13 mmol) of4-acetylthio-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one obtained inExample 142, 34.0 mg (yield: 73%) of4-mercapto-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one was obtained asa yellow oil.

[1193]¹H-NMR (300 MHz, CDCl₃)

[1194] δ: 8.21 (2H, d, J=9.2 Hz), 7.32 (2H, d, J=8.5 Hz), 7.06 (2H, d,J=8.5 Hz), 7.01 (2H, d, J=9.2 Hz), 4.54 (1H, d, J=14.9 Hz), 4.42 (1H, d,J=14.9 Hz), 3.69 (1H, dd, J=10.0, 7.2 Hz), 3.58 (1H, m), 3.20 (1H, dd,J=10.0, 5.0 Hz), 2.94 (1H, dd, J=17.1, 8.1 Hz), 2.44 (1H, dd, J=17.1,6.0 Hz), 1.89 (1H, d, J=6.6 Hz)

Example 1444-Acetylthio-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one

[1195] (1) 1.86 g (5.7 mmol) of4-hydroxy-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one prepared by amethod similar to that in Example 142 was dissolved in 40 ml ofpyridine, treated with 10 ml of acetic anhydride, and stirred at roomtemperature for 14 hours. The reaction mixture was concentrated underreduced pressure, treated with water and extracted twice with ethylacetate, and the organic layer obtained was washed with water andsaturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was precipitated fromhexane-ethyl acetate to obtain 1.80 g (yield: 85%) of4-acetoxy-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one as a tan powder.

[1196]¹H-NMR (300 MHz, CDCl₃)

[1197] δ: 8.22 (2H, d, J=9.2 Hz), 7.29 (2H, d, J=8.5 Hz), 7.07 (2}L d,J=8.5 Hz), 7.02 (2H, d, J=9.2 Hz), 5.29 (1H, m), 4.51 (2H, s), 3.68 (1H,dd, J=11.5, 6.0 Hz), 3.28 (1H, dd, J=11.5, 2.0 Hz), 2.85 (1H, dd,J=17.9, 7.2 Hz), 2.57 (1H, dd, J=17.9, 2.5 Hz), 2.06 (3H, s)

[1198] (2) 1.80 g (4.9 mmol) of4-acetoxy-1-[4-(4′-nitrophenoxy)benzyl]pyrrolidin-2-one was dissolved ina solvent mixture of 100 ml of methanol and 10 ml of tetrahydrofuran,treated with 10% Pd/C and stirred under hydrogen atmosphere at roomtemperature for 4.5 hours. The reaction mixture was filtered,concentrated under reduced pressure and treated with a 4N solution ofhydrochloric acid in ethyl acetate to obtain 1.67 g (yield: 90%) of4-acetoxy-1-[4-(4′-aminophenoxy)benzyl]pyrrolidin-2-one hydrochloride asa white powder.

[1199]¹H-NMR (300 MHz, CD₃OD)

[1200] δ: 7.35 (2H, d, J=8.9 Hz), 7.30 (2H, d, J=8.6 Hz), 7.11 (2H, d,J=8.9 Hz), 7.02 (2H, d, J=8.6 Hz), 5.27 (1H, m), 4.52 (1H, d, J=14.9Hz), 4.44 (1H d, J=14.9 Hz), 3.73 (1H, dd, J=11.7, 5.7 Hz), 3.33 (1H,dd, J=11.7, 1.5 Hz), 2.90 (1H, dd, J=18.0, 7.1 Hz), 2.47 (1H, dd,J=18.0, 1.8 Hz), 2.02 (3H, s)

[1201] (3) 324 mg (0.86 mmol) of4-acetoxy-1-[4-(4′-aminophenoxy)benzyl]pyrrolidin-2-one hydrochloridewas dissolved in 10 ml of chloroform, treated with 360 μl (2.6 mmol) oftriethylamine and 122 μl (1.7 mmol) of acetyl chloride, and stirred atroom temperature for 14 hours. The reaction mixture was concentratedunder reduced pressure, treated with ethyl acetate, washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Themixture was concentrated under reduced pressure, and the residue wassubjected to column chromatography on silica gel eluting with ethylacetate to obtain 265 mg (yield: 81%) of4-acetoxy-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one as a whitepowder.

[1202]¹H-NMR (300 MHz, CDCl₃)

[1203] δ: 7.46 (2H, d, J=8.9 Hz), 7.25 (1H, brs), 7.17 (2H, d, J=8.5Hz), 6.97 (2H, d, J=8.9 Hz), 6.93 (2H, d, J=8.5 Hz), 5.25 (1H, m), 4.48(1H, d, J=15.7 Hz), 4.42 (1H, d, J=15.7 Hz), 3.63 (1H, dd, J=11.6, 6.0Hz), 3.24 (1H, dd, J=11.6, 1.9 Hz), 2.82 (1H, dd, J=17.8, 7.2 Hz), 2.53(1H, dd, J=17.8, 2.4 Hz), 2.18 (3H, s), 2.04 (3H, s)

[1204] (4) 265 mg (0.69 mmol) of4-acetoxy-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one wasdissolved in 10 ml of ethanol and 1 ml of chloroform, treated with 330mg (3.5 mmol) of guanidine hydrochloride and 481 μl (3.5 mmol) oftriethylamine, and stirred at room temperature for 5 days. The reactionmixture was concentrated under reduced pressure, treated with ethylacetate, washed with water and saturated brine, and dried over anhydroussodium sulfate. After concentrating under reduced pressure, the residuewas precipitated from hexane-ethyl acetate to obtain 200 mg (yield: 85%)of 4-hydroxy-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one as awhite powder.

[1205]¹H-NMR (300 MHz, CDCl₃)

[1206] δ: 7.45 (2H, d, J=8.9 Hz), 7.19 (2H, d, J=8.5 Hz), 7.15 (1H,brs), 6.96 (2H, d, J=8.9 Hz), 6.92 (2H, d, J=8.5 Hz), 4.51 (1H, m), 4.47(1H, d, J=14.9 Hz), 4.40 (1H, d, J=14.9 Hz), 3.53 (1H, dd, J=10.9, 5.6Hz), 3.21 (1H, dd, J=10.9, 1.8 Hz), 2.75 (1H, dd, J=17.4, 6.6 Hz), 2.44(1H, dd, J=17.4, 2.3 Hz), 2.12 (3H, s), 2.09 (1H, brs)

[1207] (5) Then by a method similar to that in Example 30 and startingfrom 159 mg (0.47 mmol) of4-hydroxy-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one, 190 mg(yield: 46%) of4-acetylthio-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one as ayellow oil.

[1208]¹H-NMR (300 MHz, CDCl₃)

[1209] δ: 7.46 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.14 (1H,brs), 6.98 (2H, d, J=8.9 Hz), 6.93 (2H, d, J=8.5 Hz), 4.46 (1H, d,J=14.7 Hz), 4.39 (1H, d, J=14.7 Hz), 4.06 (1H, n), 3.75 (1H, dd, J=10.7,7.6 Hz), 3.18 (1H, dd, J=10.7, 4.9 Hz), 2.92 (1H, dd, J=17.4, 8.9 Hz),2.42 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s), 2.18 (3H, s)

Example 1454-Mercapto-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one

[1210] By a method similar to that in Example 31 and starting from 23.0mg (0.060 mmol) of4-acetylthio-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one obtainedin Example 144, 22.0 mg4-mercapto-1-[4-(4′-acetoaminophenoxy)benzyl]pyrrolidin-2-one wasobtained almost quantitatively as a colorless oil.

[1211]¹H-NMR (300 MHz, CD₃OD)

[1212] δ: 7.52 (2H, d, J=9.0 Hz), 7.25 (2H, d, J=8.5 Hz), 6.94 (2H, d,J=9.0 Hz), 6.94 (2H, d, J=8.5 Hz), 4.48 (1H, d, J=14.9 Hz), 4.37 (1H, d,J=14.9 Hz), 3.73 (1H, dd, J=10.4, 7.2 Hz), 3.59 (1H, n), 3.18 (1H, dd,J=10.4, 4.6 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.35 (1H, dd, J=17.1,5.4 Hz), 2.11 (3H, s), 1.29 (1H, brs)

Example 1464-Acetylthio-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-one

[1213] (1) 300 mg (0.80 mmol) of4-hydroxy-1-[4-(4′-aminophenoxy)benzyl]pyrrolidin-2-one hydrochlorideobtained in Example 144 was dissolved in 20 ml of chloroform, treatedwith 335 μl (2.4 mmol) of triethylamine and 93.0 μl (1.2 mmol) ofmethanesulfonyl chloride, and stirred at room temperature for 17 hours.The reaction mixture was concentrated under reduced pressure, treatedwith ethyl acetate, washed with water and saturated brine, and driedover anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was subjected to column chromatography on silicagel eluting with ethyl acetate to obtain 285 mg (yield: 85%) of4-acetoxy-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-one asa pale tan oil.

[1214]¹H-NMR (300 MHz, CDCl₃)

[1215] δ: 7.23 (2H, d, J=8.8 Hz), 7.21 (2H, d, 3=8.2 Hz), 6.99 (2H, d,3=8.8 Hz), 6.96 (2H, d, J=8.2 Hz), 6.55 (1H, brs), 5.27 (1H, n), 4.46(2H, s), 3.64 (1H, dd, J=11.5, 6.0 Hz), 3.25 (1H, dd, J=11.5, 2.0 Hz),3.01 (3H, s), 2.83 (1H, dd, J=17.8, 7.2 Hz), 2.55 (1H, dd, J=17.8, 2.5Hz), 2.05 (3H, s)

[1216] (2) Then by a method similar to that in Example 144 and startingfrom 285 mg (0.50 mmol) of4-acetoxy-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-one,59.0 mg (yield: 20%) of4-acetylthio-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-oneas a white powder.

[1217]¹H-NMR (300 MHz, CDCl₃)

[1218] δ: 7.22 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.6 Hz), 6.99 (2H, d,J=8.8 Hz), 6.96 (2H, d, J=8.6 Hz), 6.27 (1H, brs), 4.44 (2H, s), 4.06(1H, m), 3.76 (1H, dd, J=10.7, 7.7 Hz), 3.18 (1H, dd, J=10.7, 5.0 Hz),3.01 (3H, s), 2.92 (1H, dd, J=17.4, 9.0 Hz), 2.42 (1H, dd, J=17.4, 6.0Hz), 2.32 (3H, s)

Example 1474-Mercapto-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-one

[1219] By a method similar to that in Example 31 and starting from 38.0mg (0.090 mmol) of4-acetylthio-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-oneobtained in Example 146, 28.0 mg (yield: 79%) of4-mercapto-1-[4-(4′-methylsulfonylaminophenoxy)benzyl]pyrrolidin-2-onewas obtained as a white powder.

[1220]¹H—NMR (300 MHz, CDCl₃)

[1221] δ: 7.22 (2H, d, J=8.7 Hz), 7.21 (2H, d, J=9.0 Hz), 6.99 (2H, d,J=9.0 Hz), 6.96 (2H, d, J=8.7 Hz), 6.33 (1H, s), 4.49 (1H, d, J=14.7Hz), 4.40 (1H, d, J=14.7 Hz), 3.66 (1H, dd, J=10.0, 7.2 Hz), 3.55 (1H,m), 3.17 (1H, dd, J=10.0, 5.0 Hz), 3.00 (3H, s), 2.92 (1H, dd, J=17.1,8.1 Hz), 2.42 (1H, dd, J=17.1, 6.0 Hz), 1.87 (1H, d, J=6.7 Hz)

Example 1484-Acetylthio-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-one

[1222] (1) 300 mg (0.80 mmol) of4-hydroxy-1-[4-(4′-aminophenoxy)benzyl]pyrrolidin-2-one hydrochlorideobtained in Example 144 was dissolved in 10 ml of chloroform, treatedwith 233 μl (1.6 mmol) of triethylamine and 317 μl (3.2 mmol) of ethylcyanate, and stirred at room temperature for 14 hours. The reactionmixture was concentrated under reduced pressure, treated with ethylacetate, washed with water and saturated brine, and dried over anhydroussodium sulfate. After concentrating under reduced pressure, the residuewas subjected to column chromatography on silica gel eluting withhexane-ethyl acetate (30:70-0:100) to obtain 278 mg (yield: 85%) of4-acetoxy-1-[4-(4′ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-oneas a white powder.

[1223]¹H-NMR (300 MHz, CDCl₃)

[1224] δ: 7.26 (2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.4 Hz), 6.93 (2H, d,J=8.7 Hz), 6.92 (2H, d, J=8.4 Hz), 6.66 (1H, s), 5.26 (1H, n), 4.91 (1H,brs), 4.45 (2H, s), 3.64 (1H, dd, J=11.6, 6.0 Hz), 3.27 (3H, m), 2.82(1H, dd, J=17.8, 7.2 Hz), 2.54 (1H, dd, J=17.8, 2.3 Hz), 2.04 (3H, s),1.16 (3H, t, J=7.0 Hz)

[1225] (2) Then by a method similar to that in Example 30 and startingfrom 278 mg (0.68 mmol) of4-acetoxy-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-one,107 mg (yield: 37%) of4-acetylthio-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-onewas obtained as a white powder.

[1226]¹H-NMR (300 MHz, CDCl₃)

[1227] δ 7.26 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.5 Hz), 6.97 (2H, d,J=8.8 Hz), 6.94 (2H, d, J=8.5 Hz), 6.29 (1H, brs), 4.66 (1H, brt), 4.46(1H, d, J=14.8 Hz), 4.39 (1H, d, J=14.8 Hz), 4.06 (1H, m), 3.76 (1H, dd,J=10.6, 7.5 Hz), 3.30 (2H, m), 3.17 (1H, dd, J=10.6, 5.0 Hz), 2.92 (1H,dd, J=17.4, 8.9 Hz), 2.42 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s), 1.16(3H, t, J=7.2 Hz)

Example 1494-Mercapto-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-one

[1228] By a method similar to that in Example 31 and starting from 27.0mg (0.060 mmol) of4-acetylthio-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-oneobtained in Example 148, 6.00 mg (yield: 26%) of4-mercapto-1-[4-(4′-ethylaminocarbonylaminophenoxy)benzyl]pyrrolidin-2-onewas obtained as a pale tan oil.

[1229]¹H-NMR (300 MHz, CDCl₃)

[1230] δ: 7.26 (2H, d, J=8.7 Hz), 7.18 (2H, d, J=8.5 Hz), 6.95 (2H, d,J=8.7 Hz), 6.93 (2H, d, J=8.5 Hz), 6.47 (1H, s), 4.78 (1H, t, J=5.7 Hz),4.46 (1H, d, J=14.8 Hz), 4.39 (1H, d, J=14.8 Hz), 3.66 (1H, dd, J=10.1,7.3 Hz), 3.54 (1H, m), 3.29 (2H, qd, J=7.1, 5.7 Hz), 3.17 (1H, dd,J=10.1, 5.0 Hz), 2.91 (1H, dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1,6.1 Hz), 1.87 (1H, d, J=6.7 Hz), 1.15 (3H, t, J=7.1 Hz)

Example 150 4-Acetylthio-1-(2-nitro-4-phenoxybenzyl)pyrrolidin-2-one

[1231] (1) 5.00 g (27 mmol) of 4-chloro-2-nitrobenzaldehyde wasdissolved in 50 ml of pyridine, treated with 3.80 g (40 mmol) of phenoland 7.40 g (54 mmol) of potassium carbonate, and heated at 100° C. for2.5 hours. Then 5.30 g (67 mmol) of copper (II) oxide was added and themixture was heated at 120° C. for 15.5 hours. The reaction mixture wasconcentrated under reduced pressure, treated with ethyl acetate, andfiltered to remove insolubles. The filtrate was washed with saturatedaqueous sodium carbonate, water and saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel elutingwith hexane-ethyl acetate (97:3) to obtain 4.80 g (yield: 73%) of2-nitro-4-phenoxybenzaldehyde as a yellow oil.

[1232]¹H-NMR (300 MHz, CDCl₃)

[1233] δ: 10.48 (1H, s), 7.88 (1H, d, J=8.4 Hz), 7.45 (1H, d, J=7.5 Hz),7.43 (1H, d, J=7.5 Hz), 7.25 (1H, dd, J=7.4, 7.4 Hz), 7.14 (1H, dd,J=8.4, 1.8 Hz), 7.10 (2H, d, J=8.7 Hz), 7.10 (2H, d, J=8.7 Hz), 6.89(1H, d, J=1.8 Hz)

[1234] (2) Then by a method similar to that in Example 30 and startingfrom 2-nitro-4-phenoxybenzyl chloride,4-acetylthio-1-(2-nitro-4-phenoxybenzyl)pyrrolidin-2-one was obtained asa colorless oil (yield: 11%).

[1235]¹H-NMR (300 MHz, CDCl₃)

[1236] δ: 7.39 (1H, d, J=8.2 Hz), 7.35 (1H, d, J=7.8 Hz), 7.27 (1H, d,J=7.5 Hz), 7.15 (1H, ddd, J=7.5, 7.5, 0.5 Hz), 7.08 (1H, dd, J=8.2, 2.0Hz), 6.96 (2H, dd, J=7.8, 0.5 Hz), 6.84 (1H, d, J=2.0 Hz), 4.51 (2H, s),4.02 (1H, m), 3.81 (1H, dd, J=10.7, 7.6 Hz), 3.23 (1H, dd, J=10.7, 4.9Hz), 2.83 (1H, dd, J=17.4, 8.9 Hz), 2.34 (1H, dd, J=17.4, 6.0 Hz), 2.32(3H, s)

Example 151 4-Acetylthio-1-(3-nitro-4-phenoxybenzyl)pyrrolidin-2-one

[1237] (1) 1.90 g (40 mmol) of sodium hydride (60% in oil) was dispersedin 20 ml of N,N-dimethylformamide, and stirred at room temperature for10 minutes. A solution of 3.80 g (40 mmol) of phenol in 20 ml ofN,N-dimethylformamide was added, and the mixture was stirred at roomtemperature further for 10 minutes. To this solution, 7.40 g (40 mmol)of 4-chloro-3-nitrobenzaldehyde was added, and the mixture was stirredat room temperature for 10 minutes and then at 120° C. for 1 hour withheating. The reaction mixture was treated with ethyl acetate, washedwith water and saturated brine, and then dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wassubjected to column chromatography on silica gel eluting withhexane-ethyl acetate (90:10) to obtain 6.50 g (yield: 67%) of3-nitro-4-phenoxybenzaldehyde as a yellow oil.

[1238]¹H-NMR (300 MHz, CDCl₃)

[1239] δ: 9.97 (1H, s), 8.44 (1H, d, J=2.1 Hz), 7.97 (1H, dd, J=8.8, 2.1Hz), 7.48 (2H, d, J=7.7 Hz), 7.45 (1H, d, J=7.4 Hz), 7.30 (1H, dd,J=7.4, 7.4 Hz), 7.14 (1H, d, J=7.7 Hz), 7.05 (1H, d, J=8.8 Hz)

[1240] (2) Then by a method similar to that in Example 30 and startingfrom 1.04 g (3.9 mmol) of 3-nitro-4-phenoxybenzyl chloride, 344 mg(yield: 20%) of 4-acetylthio-1-(3-nitro-4-phenoxybenzyl)pyrrolidin-2-onewas obtained as a pale yellow oil.

[1241]¹H-NMR (300 MHz, CDCl₃)

[1242] δ: 7.82 (1H, d, J=2.]Hz), 7.41 (1H, d, J=8.6 Hz), 7.38 (2H, d,J=7.9 Hz), 7.20 (1H, dd, J=7.4, 7.4 Hz), 7.06 (2H, d, J=7.9 Hz), 6.98(1H, d, J=8.6 Hz), 4.55 (1H, d, J=15.1 Hz), 4.40 (1H, d, J=15.1 Hz),4.08 (1H, m), 3.81 (1H, dd, J=10.5, 7.4 Hz), 3.22 (1H, dd, J=10.5, 4.7Hz), 2.93 (1H, dd, J=17.5, 8.9 Hz), 2.44 (1H, dd, J=17.5, 5.7 Hz), 2.34(3H, s)

Example 1524-Acetylthio-1-(3-methylsulfonylamino-4-phenoxybenzyl)pyrrolidin-2-one

[1243] 3-Nitro-4-phenoxybenzaldehyde synthesized in Example 151 wasprocessed similarly to Example 146 to obtain4-acetylthio-1-(3-methylsulfonylamino-4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil (yield: 5%).

[1244]¹H-NMR (300 MHz, CDCl₃)

[1245] δ: 7.49 (1H, d, J=1.9 Hz), 7.40 (1H, d, J=7.9 Hz), 7.36 (1H, d,J=8.1 Hz), 7.19 (1H, dd, J=7.9, 7.9 Hz), 7.00 (2H, d, J=8.1 Hz), 6.97(1H, dd, J=8.3, 1.9 Hz), 6.85 (1H, d, J=8.3 Hz), 6.85 (1H, brs), 4.44(2H, s), 4.07 (1H, m), 3.79 (1H, dd, J=10.6, 7.5 Hz), 3.22 (1H, dd,J=10.6, 5.0 Hz), 3.01 (3H, s), 2.92 (1H, dd, J=17.4, 9.0 Hz), 2.43 (1H,dd, J=17.4, 6.1 Hz), 2.33 (3H, s)

Example 1534-Mercapto-1-(3-methylsulfonylamino-4-phenoxybenzyl)pyrrolidin-2-one

[1246] By a method similar to that in Example 31 and starting from 39.0mg (0.090 mmol) of4-acetylthio-1-(3-methylsulfonylamino-4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 152, 34.0 mg (yield: 97%) of4-mercapto-1-(3-methylsulfonylamino-4-phenoxybenzyl)pyrrolidin-2-one wasobtained as a colorless oil.

[1247]¹H-NMR (300 MHz, CDCl₃)

[1248] δ: 7.50 (1H, d, J=2.0 Hz), 7.39 (1H, d, J=7.5 Hz), 7.36 (1H, d,J=8.1 Hz), 7.18 (1H, dd, J=7.5, 7.5 Hz), 6.99 (3H, m), 6.86 (1H, d,J=8.3 Hz), 6.85 (1H, brs), 4.51 (1H, d, J=15.0 Hz), 4.40 (1H, d, J=15.0Hz), 3.71 (1H, dd, J=10.1, 7.2 Hz), 3.57 (1H, m), 3.22 (1H, dd, J=10.1,5.0 Hz), 3.01 (3H, s), 2.93 (1H, dd, J=17.2, 8.2 Hz), 2.43 (1H, dd,J=17.2, 6.0 Hz), 1.91 (1H, d, J=6.9 Hz)

Example 154 4-Acetylthio-1-(4-phenylthiobenzyl)pyrrolidin-2-one

[1249] By a method similar to that in Example 30 and starting from 1.61g (6.9 mmol) of 4-phenylthiobenzyl chloride prepared from4-fluorobenzaldehyde and thiophenol and 1.80 g (10 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 716 mg (yield: 29%) of4-acetylthio-1-(4-phenylthiobenzyl)pyrrolidin-2-one was obtained as atan oil.

[1250] Elemental analysis (%): C₁₉H₁₉NO₂S₂

[1251] Calcd.: C, 63.83; H, 5.36; N, 3.92; S, 17.94

[1252] Found: C, 63.86; H, 5.11; N, 3.99; S, 17.77

Example 155 4-Mercapto-1-(4-phenylthiobenzyl)pyrrolidin-2-one

[1253] By a method similar to that in Example 31 and starting from 130mg (0.36 mmol) of 4-acetylthio-1-(4-phenylthiobenzyl)pyrrolidin-2-oneobtained in Example 154, 69.0 mg (yield: 61%) of4-mercapto-1-(4-phenylthiobenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[1254]¹H-NMR (300 MHz, CDCl₃)

[1255] δ: 7.38-7.26 (7H, m), 7.17 (2H, d, J=8.3 Hz), 4.47 (1H, d, J=14.9Hz), 4.40 (1H, d, J=14.9 Hz), 3.64 (1H, dd, J=10.0, 7.2 Hz), 3.54 (1H,m), 3.16 (1H, dd, J=10.0, 5.0 Hz), 2.92 (1H, dd, J=17.1, 8.1 Hz), 2.42(1H, dd, J=17.1, 6.1 Hz), 1.86 (1H, d, J=6.7 Hz),

Example 156 4-Acetylthio-1-[4-(2′-pyridyloxy)benzyl]pyrrolidin-2-one

[1256] By a method similar to that in Example 30 and starting from 420mg (1.9 mmol) of 4-(2′-pyridyloxy)benzyl chloride prepared from4-fluorobenzaldehyde and 2-hydroxypyridine and 494 mg (2.9 mmol) of4-trimethylsilyloxypyrrolidin-2-one, 47.0 mg (yield: 7%) of4-acetylthio-1-[4-(2′-pyridyloxy)benzyl]pyrrolidin-2-one was obtained asa pale yellow powder.

[1257]¹H-NMR (300 MHz, CDCl₃)

[1258] δ:8.20 (1H, dd, J=.5.0, 1.9 Hz), 7.70 (1H, ddd, J=8.8, 6.9, 1.9Hz), 7.26 (2H, d, J=8.5 Hz), 7.11 (2H, d, J=8.5 Hz), 7.00 (1H, dd,J=6.9, 5.0 Hz), 6.92 (1H, d, J=8.8 Hz), 4.50 (1H, d, J=14.7 Hz), 4.42(1H, d, J=14.7 Hz), 4.07 (1H, m), 3.78 (1H, dd, J=10.6, 7.6 Hz), 3.21.(1H, dd, J=10.6, 5.0 Hz), 2.93 (1H, dd, J=17.4, 9.0 Hz), 2.43 (1H, dd,J=17.4, 6.0 Hz), 2.32 (3H, s)

Example 157 4-Acetylthio-1-[4-(3′-thienyloxy)benzyl]pyrrolidin-2-one

[1259] (1) 7.50 g (61 mmol) of 4-hydroxybenzaldehyde, 10.0 g (61 mmol)of 3-bromothiophene, 3.40 g (25 mmol) of potassium carbonate and 500 mgof copper turnings were treated and heated as neat at 140° C. for 44hours. The reaction mixture was poured into an aqueous solution ofsodium hydroxide and extracted three times with ethyl acetate, and theorganic layer obtained was washed with a saturated aqueous solution ofsodium carbonate, water and saturated brine, and then dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel elutingwith hexane-ethyl acetate (70:30) to obtain 1.70 g (yield: 14%) of4-(3′-thienyloxy)benzaldehyde as a yellow oil.

[1260]¹H-NMR (300 MHz, CDCl₃)

[1261] δ 9.93 (1H, s), 7.85 (2H, d, J=8.6 Hz), 7.33 (1H, dd, J=5.1, 3.3Hz), 7.11 (2H, d, J=8.6 Hz), 6.87 (1H, dd, J=5.1, 1.4 Hz), 6.84 (1H, dd,J=3.3, 1.4 Hz)

[1262] (2) Then by a method similar to that in Example 30 and startingfrom 1.30 g (5.8 mmol) of 4-(3′-thienyloxy)benzyl chloride and 1.20 g(7.0 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 521 mg (yield: 26%)of 4-acetylthio-1-[4-(3′-thienyloxy)benzyl]pyrrolidin-2-one was obtainedas a tan oil.

[1263]¹H-NMR (300 MHz, CDCl₃)

[1264] δ: 7.26 (1H, dd, J=5.2, 3.3 Hz), 7.18 (2H, d, J=8.6 Hz), 7.00(2H, d, J=8.6 Hz), 6.85 (1H, dd, J=5.2, 1.5 Hz), 6.62 (1H, dd, J=3.3,1.5 Hz), 4.46 (1H, d, J=14.7 Hz), 4.39 (1H, d, J=14.7 Hz), 4.05 (1H, m),3.75 (1H, dd, J=10.6, 7.6 Hz), 3.16 (1H, dd, J=10.6, 5.0 Hz), 2.92 (1H,dd, J=17.4, 9.0 Hz), 2.42 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s)

Example 158 4-Mercapto-1-[4-(3′-thienyloxy)benzyl]pyrrolidin-2-one

[1265] By a method similar to that in Example 31 and starting from 100mg (0.30 mmol) of4-acetylthio-1-[4-(3′-thienyloxy)benzyl]pyrrolidin-2-one obtained inExample 157, 74.0 mg (yield: 81%) of4-mercapto-1-[4-(3′-thienyloxy)benzyl]pyrrolidin-2-one was obtained as acolorless oil.

[1266]¹H-NMR (300 MHz, CDCl₃)

[1267] δ: 7.27 (1H, dd, J=5.2, 3.2 Hz), 7.20 (2H, d, J=8.6 Hz), 7.01(2H, d, J=8.6 Hz), 6.84 (1H, dd, J=5.2, 1.5 Hz), 6.63 (1H, dd, J=3.2,1.5 Hz), 4.47 (1H, d, J=14.7 Hz), 4.40 (1H, d, J=14.7 Hz), 3.65 (1H, dd,J=10.0, 7.2 Hz), 3.54 (1H, m), 3.16 (1H, dd, J=10.0, 5.0 Hz), 2.92 (1H,dd, J=17.1, 8.1 Hz), 2.42 (1H, dd, J=17.1, 6.1 Hz), 1.86 (1H, d, J=6.7Hz)

Example 159 4-Acetylthio-1-(4-benzylbenzyl)pyrrolidin-2-one

[1268] (1) 5.07 g (22.4 mmol) of 4-benzoylbenzoic acid was dis-solved in50 ml of N,N-dimethylformamide, treated with 3.10 g (22.4 mmol) ofpotassium carbonate and 2.79 ml (44.8 mmol) of methyl iodide and thenstirred at room temperature for 14 hours. The reaction mixture wasconcentrated under reduced pressure, treated with ethyl acetate, washedwith water and saturated brine, and then dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wascrystallized from hexane-ethyl acetate to obtain 4.28 g (yield: 80%) ofmethyl 4-benzoylbenzoate as a colorless needle.

[1269]¹H-NMR (300 MHz, CDCl₃)

[1270] δ: 8.15 (2H, d, J=8.3 Hz), 7.84 (2H, d, J=8.3 Hz), 7.81 (2H, m),7.62 (1H, m), 7.50 (2H, m), 3.97 (3H, s)

[1271] (2) To a mixture of 24 ml of chloroform and 40 ml oftrifluoroacetic acid, 1.89 g (49.9 mmol) of sodium borohydride was addedand then 2.00 g (8.32 mmol) of methyl 4-benzoylbenzoate was added, andthe mixture was stirred at room temperature for 5 hours, and 945 mg(25.0 mmol) of sodium borohydride was further added and stirred for 16hours. The reaction mixture was concentrated under reduced pressure,treated with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate, water and saturated brine, and then dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel, andthe fraction eluted with hexane:ethyl acetate (100:0-90:10) wasconcentrated under reduced pressure to obtain 1.81 g (yield: 96%) ofmethyl 4-benzylbenzoate as a colorless oil.

[1272]¹H-NMR (300 MHz, CDCl₃)

[1273] δ: 7.95 (2H, d, J=8.3 Hz), 7.15-7.33 (7H, m), 4.03 (2H, s), 3.89(3H, s)

[1274] (3) 1.76 g (7.78 mmol) of methyl 4-benzylbenzoate was dissolvedin 40 ml of diethyl ether, treated with 591.mg (15.6 mmol) of lithiumaluminum hydride and stirred at room temperature for 1 hour. Thereaction mixture was treated with water with cooling on ice andextracted three times with ethyl acetate, and the ethyl acetate layerwas washed twice with water and once with saturated brine, and driedover anhydrous sodium sulfate. The mixture was concentrated underreduced pressure to obtain 1.57 g (quantitative yield) of4-benzylbenzylalcohol as a colorless oil.

[1275]¹H-NMR (300 MHz, CDCl₃)

[1276] δ: 7.28 (4H, m), 7.19 (5H, n), 4.65 (2H, s), 3.98 (2H, s)

[1277] (4) 1.52 g (7.67 mmol) of 4-benzylbenzylalcohol was dissolved inchloroform, and 620 μl (7.67 mmol) of pyridine was added with cooling onice, and a solution of 615 μl (8.44 mmol) of thionyl chloride in 5 ml ofchloroform was added dropwise over a period of 30 minutes, and then themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, treated with ethyl acetate,washed with water and saturated brine, and dried over anhydrous sodiumsulfate. The mixture was concentrated under reduced pressure to obtain1.68 g (quantitative yield) of 4-benzylbenzyl chloride as a colorlessoil.

[1278]¹H-NMR (300 MHz, CDCl₃)

[1279] δ: 7.29 (4H, m), 7.19 (5H, m), 4.56 (2H, s), 3.98 (2H, s)

[1280] (5) Similarly to Example 30 and starting from 1.60 g (7.38 mmol)of 4-benzylbenzyl chloride, 1.28 g (7.38 mmol) of4-trimethylsilyloxypyrrolidin-2-one and 414 mg (7.38 mmol) of powderedpotassium hydroxide, 510 mg (yield: 25%) of4-hydroxy-1-(4-benzylbenzyl)pyrrolidin-2-one was obtained as a whitepowder.

[1281]¹H-NMR (300 MHz, CDCl₃)

[1282] δ: 7.28 (2H, m), 7.13-7.23 (7H, m), 4.47 (1H, m), 4.44 (2H, s),3.95 (2H, s), 3.49 (1H, dd, J=10.9, 5.7 Hz), 3.18 (1H, dd, J=10.9, 1.9Hz), 2.73 (1H, dd, J=17.3, 6.4 Hz), 2.42 (1H, dd, J=17.3, 2.3 Hz), 2.14(1H, brs)

[1283] (6) Starting from 460 mg (1.63 mmol) of4-hydroxy-1-(4-benzylbenzyl)pyrrolidin-2-one, 454 μl (3.26 mmol) oftriethylamine and 252 μl (3.26 mmol) of methanesulfonyl chloride, 534 mg(yield: 91%) of 4-methanesulfonyloxy-1-(4-benzylbenzyl)pyrrolidin-2-onewas obtained as a white powder.

[1284]¹H-NMR (300 MHz, CDCl₃)

[1285] δ: 7.29 (2H, m), 7.13-7.23 (7H, m), 5.26 (1H, m), 4.48 (1H, d,J=14.9 Hz), 4.43 (1H, d, J=14.9 Hz), 3.96 (2H, s), 3.63 (1H, dd, J=11.7,5.7 Hz), 3.49 (1H, dd, J=11.7, 2.1 Hz), 2.95 (3H, s), 2.86 (1H, dd,J=18.1, 6.8 Hz), 2.70 (1H, dd, J=18.1, 2.6 Hz)

[1286] (7) Starting from 500 mg (1.39 mmol) of4-methanesulfonyloxy-1-(4-benzylbenzyl)pyrrolidin-2-one and 318 mg (2.78mmol) of potassium thioacetate, 331 mg (yield: 70%) of4-acetylthio-1-(4-benzylbenzyl)pyrrolidin-2-one was obtained as a whitepowder.

[1287]¹H-NMR (300 MHz, CDCl₃)

[1288] δ: 7.29 (2H, m), 7.13-7.23 (7H, m), 4.42 (2H, s), 4.04 (1H, m),3.96 (2H, s), 3.72(1H, dd, J=10.9, 7.5 Hz), 3.15 (1H, dd, J=10.9, 5.1Hz), 2.91 (1H, dd, J=17.3, 9.1 Hz), 2.41 (1H, dd, J=17.3, 6.0 Hz), 2.30(3H, s)

Example 160 4-Mercapto-1-(4-benzylbenzyl)pyrrolidin-2-one

[1289] 200 mg (0.589 mmol) of4-acetylthio-1-(4-benzylbenzyl)pyrrolidin-2-one obtained in Example 159was processed similarly to Example 31 to obtain 147 mg (yield: 84%) of4-mercapto-1-(4-benzylbenzyl)pyrrolidin-2-one as a white powder.

[1290]¹H-NMR (300 MHz, CDCl₃)

[1291] δ: 7.29 (2H, m), 7.13-7.23 (7H, i), 4.43 (2H, s), 3.97 (2H, s),3.62 (1H, dd, J=9.8, 7.2 Hz), 3.51 (1H, m), 3.14 (1H, dd, J=9.8, 5.1Hz), 2.90 (1H, dd, J=17.0, 8.3 Hz), 2.41 (1H, dd, J=17.0, 6.2 Hz), 1.85(1H, d, J=6.8 Hz)

Example 161 4-Acetylthio-1-(4-benzoylbenzyl)pyrrolidin-2-one

[1292] (1) 2.00 g (8.32 mmol) of methyl 4-benzoylbenzoate obtained inExample 159 was dissolved in 25 ml of nitromethane, treated with 9.10 ml(83.2 mmol) of trimethyl o-formate, 3.37 ml (83.2 mmol) of absolutemethanol and 147 μl (1.66 mmol) of trifluoromethanesulfonic acid, heatedunder reflux for 4 hours with stirring, treated further with 9.10 ml(83.2 mmol) of trimethyl orthoformate, and 3.37 ml (83.2 mmol) ofabsolute methanol, and heated under ref lux for 16 hours with stirring.The reaction mixture was treated with saturated aqueous sodium hydrogencarbonate and extracted twice with ethyl acetate, and the ethyl acetatelayer was washed twice with water and once with saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was subjected to column chromatography on silicagel eluting with hexane:ethyl acetate (95:5) to obtain4-methoxycarbonylbenzophenone dimethylacetal, and 680 mg of the startingmethyl ester was recovered using hexane:ethyl acetate (90:10). Thestarting material recovered was subjected to the reaction again andcombined with 4-methoxycarbonylbenzophenone dimethylacetal to obtain2.32 g (yield: 97%) as a colorless oil.

[1293]¹H-NMR (300 MHz, CDCl₃)

[1294] δ: 7.96 (2H, d, J=8.7 Hz), 7.58 (2H, d, J=8.7 Hz), 7.48 (2H, m),7.19-7.33 (3H, n), 3.88 (3H, s), 3.13 (6H, s)

[1295] (2) Starting from 2.27 g (7.93 mmol) of4-methoxycarbonylbenzophenone dimethylacetal and 602 mg (15.9 mmol) oflithium aluminum hydride and similarly to Example 159, 2.05 g(quantitative yield) of 4-hydroxymethylbenzophenone dimethylacetal as acolorless oil.

[1296]¹H-NMR (300 MHz, CDCl₃)

[1297] δ: 7.50 (4H, m), 7.29 (4H, m), 7.21 (1H, m), 4.65 (2H, s), 3.13(6H, s)

[1298] (3) 2.00 g (7.74 mmol) of 4-hydroxymethylbenzophenonedimethylacetal, 626 μl (7.74 mmol) of pyridine and 621 μl (8.51 mmol) ofthionyl chloride were processed similarly to Example 159, 930 mg (yield:52%) of 4-benzoylbenzyl chloride was obtained as a colorless oil.

[1299]¹H-NMR (300 MHz, CDCl₃)

[1300] δ: 7.81 (4H, m), 7.59 (1H, m), 7.51 (4H, m), 4.65 (2H, s)

[1301] (4) Starting from 900 mg (3.90 mmol) of 4-benzoylbenzyl chloride,535 mg (3.90 mmol) of 4-trimethylsilyloxypyrrolidin-2-on and 219 mg(3.90 mmol) of powdered potassium hydroxide, 200 mg (yield: 17%) of4-hydroxy-1-(4-benzoylbenzyl)pyrrolidin-2-one was obtained as a tanpowder.

[1302]¹H-NMR (300 MHz, CDCl₃)

[1303] δ: 7.79 (4H, m), 7.60 (1H, m), 7.48 (2H, m), 7.36 (2H, d, J=8.3Hz), 4.64 (1H, d, J=15.3 Hz), 4.55 (1H, m), 4.51 (1H, d, J=15.3 Hz),3.57 (1H, dd, J=10.9, 5.7 Hz), 3.24 (1H, dd, J=10.9, 2.1 Hz), 2.78 (1H,dd, J=17.3, 6.4 Hz), 2.47 (1H, dd, J=17.3, 2.3 Hz), 1.99 (1H, brs)

[1304] (5) Starting from 180 mg (0.609 mmol) of4-hydroxy-1-(4-benzoylbenzyl)pyrrolidin-2-one, 170 μl (1.22 mmol) oftriethylamine and 94.3 μl (1.22 mmol) of methanesulfonyl chloride, 249mg (quantitative yield) of4-methanesulfonyloxy-1-(4-benzoylbenzyl)pyrrolidin-2-one was obtained asa colorless oil.

[1305]¹H-NMR (300 MHz, CDCl₃)

[1306] δ: 7.79 (4H, m), 7.61 (1H, m), 7.49 (2H, m), 7.35 (2H, d, J=7.9Hz), 5.32 (1H, m), 4.61 (1H, d, J=15.1 Hz), 4.55 (1H, d, J=15.1 Hz),3.71 (1H, dd, J=11.9, 5.9 Hz), 3.57 (1H, dd, J=1.9, 1.9 Hz), 3.04 (3H,s), 2.91 (1H, dd, J=18.1, 6.8 Hz), 2.75 (1H, dd, J=18.1, 2.5 Hz)

[1307] (6) Starting from 227 mg (0.609 mmol) of4-methanesulfonyloxy-1-(4-benzoylbenzyl)pyrrolidin-2-one and 140 mg(1.23 mmol) of potassium thioacetate, 138 mg (yield: 64%) of4-acetylthio-1-(4-benzoylbenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[1308]¹H-NMR (300 MHz, CDCl₃)

[1309] δ: 7.80 (4H, m), 7.61 (1H, m), 7.49 (2H, m), 7.35 (2H, d, J=8.3Hz), 4.61 (1H, d, J=5.1 Hz), 4.48 (1H, d, J=15.1 Hz), 4.09 (1H, m), 3.80(1H, dd, J=10.6, 7.5 Hz), 3.21 (1H, dd, J=10.6, 4.9 Hz), 2.96 (1H, dd,J=17.5, 9.9 Hz), 2.46 (1H, dd, J=17.5, 5.9 Hz), 2.32 (3H, s)

Example 162 4-Mercapto-1-(4-benzoylbenzyl)pyrrolidin-2-one

[1310] 108 mg (0.306 mmol) of4-acetylthio-1-(4-benzoylbenzyl)pyrrolidin-2-one obtained in Example 161was processed similarly to Example 31 to obtain 77.2 mg (yield: 81%) of4-mercapto-1-(4-benzoylbenzyl)pyrrolidin-2-one as a colorless oil.

[1311]¹H-NMR (300 MHz, CDCl₃)

[1312] δ: 7.80 (4H, m), 7.60 (1H, m), 7.49 (2H, m), 7.37 (2H, d, J=8.3Hz), 4.61 (1H, d, J=15.1 Hz), 4.51 (1H, d, J=15.1 Hz), 3.69 (1H, dd,J=10.0, 7.2 Hz), 3.59 (1H, m), 3.20 (1H, dd, J=10.0, 4.9 Hz), 2.95 (1H,dd, J=17.2, 8.1 Hz), 2.45 (1H, dd, J=17.2, 6.9 Hz), 1.90 (1H, d, J=6.4Hz)

Example 163 4-Acetylthio-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one

[1313] (1) 5.00 g (30.1 mmol) of methyl 4-hydroxymethylbenzoate wasdissolved in 75 ml of chloroform, and 2.43 ml (30.1 mmol) of pyridinewas added with cooling on ice, and then a solution of 2.42 ml (33.1mmol) of thionyl chloride in 10 ml of chloroform was added dropwise overa period of 30 minutes, and then the mixture was stirred with cooling onice for 30 minutes and 2 hours at room temperature. The reaction mixturewas concentrated under reduced pressure, treated with ethyl acetate,washed twice with water and once with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was dissolved in 75 ml of N,N-dimethylformamide, treatedwith 2.83 g (30.1 mmol) of phenol and 4.16 g (30.1 mmol) of potassiumcarbonate, and stirred at room temperature for 40 hours. The reactionmixture was concentrated under reduced pressure, treated with ethylacetate, washed twice with water and once with saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was subjected to column chromatography on silicagel, and the fraction eluted with hexane:ethyl acetate (95:5) wasconcentrated under reduced pressure, and crystallized from hexane-ethylacetate to obtain 5.35 g (yield: 73%) of methyl 4-phenoxymethylbenzoateas a colorless needle.

[1314]¹H-NMR (300 MHz, CDCl₃)

[1315] δ: 8.06 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.3 Hz), 7.30 (2H, m),6.96 (3H, m), 5.13 (2H, s), 3.92 (3H, s)

[1316] (2) Starting from 5.35 g (22.1 mmol) of methyl4-phenoxymethylbenzoate and 839 mg (22.1 mmol) of lithium aluminumhydride and similarly to Example 159, 4.22 g (yield: 89%) of4-phenoxymethylbenzylalcohol was obtained as a white powder.

[1317]¹H-NMR (300 MHz, CDCl₃)

[1318] δ: 7.41 (4H, m), 7.29 (2H, m), 6.96 (3H, m), 5.07 (2H, s), 4.70(2H, s)

[1319] (3) 2.00 g (9.33 mmol) of 4-phenoxymethylbenzylalcohol, 755 μl(9.33 mmol) of pyridine and 749 μl (10.3 mmol) of thionyl chloride wereprocessed similarly to Example 159 to obtain 2.20 g (quantitative yield)of 4-phenoxymethylbenzyl chloride as a colorless oil.

[1320]¹H-NMR (300 MHz, CDCl₃)

[1321] δ: 7.42 (4H, m), 7.29 (2H, m), 6.97 (3H, m), 5.07 (2H, s), 4.60(2H, s)

[1322] (4) Similarly to Example 30 and starting from 1.40 g (6.00 mmol)of 4-phenoxymethylbenzyl chloride, 1.04 g (6.00 mmol) of4-trimethylsilyloxypyrrolidin-2-one and 396 mg (7.06 mmol) of powderedpotassium hydroxide, 710 mg (yield: 40%) of4-hydroxy-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one was obtained as awhite powder.

[1323] Elemental analysis (%): C₁₈H₁₉NO₃

[1324] Calcd.: C, 72.712; H, 6.44; N, 4.71

[1325] Found: C, 72.46; H, 6.45;N, 4.54

[1326] (5) Starting from 650 mg (2.19 mmol) of4-hydroxy-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one, 610 μl (4.38 mmol)of triethylamine and. 339 μl (4.38 mmol) of methanesulfonyl chloride,760 mg (yield: 92%) of4-methanesulfonyloxy-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one wasobtained as a white powder.

[1327] Elemental analysis (%): C₁₉H₂₁NO₅S·0.1H₂O

[1328] Calcd.: C, 60.49; H, 5.66; N, 3.71

[1329] Found: C, 60.46; H, 5.84; N, 3.61

[1330] (6) Starting from 710 mg (1.89 mmol) of4-methanesulfonyloxy-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one and 432mg (3.78 mmol) of potassium thioacetate, 464 mg (yield: 69%) of4-acetylthio-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one was obtained as awhite powder.

[1331]¹H-NMR (300 MHz, CDCl₃)

[1332] δ: 7.42 (2H, d, J=7.9 Hz), 7.23-7.34 (4H, m), 6.97 (3H, m), 5.05(2H, s), 4.51 (1H, d, J=14.7 Hz), 4.42 (1H, d, J=14.7 Hz), 4.05 (1H, n),3.75 (1H, dd, J=10.6, 7.5 Hz), 3.17 (1H, dd, J=110.6, 4.9 Hz), 2.93 (1H,dd, J=17.3, 8.9 Hz), 2.43 (1H, dd, J=17.3, 6.0 Hz), 2.31 (3H, s)

Example 164 4-Mercapto-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one

[1333] 230 mg (0.647 nmol) of4-acetylthio-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one obtained inExample 163 was dissolved in 23 ml of methanol, treated with 132 μl(0.647 mmol) of a 28% solution of sodium methoxide in methanol, andstirred at room temperature for 0.5 hour. The reaction mixture wasadjusted at pH 2.0, concentrated under reduced pressure, treated withethyl acetate, washed twice with water and once with saturated brine,and dried over anhydrous sodium sulfate. After concentrating underreduced pressure, the mixture was precipitated from hexane-ethyl acetateto obtain 156 mg (yield: 77%) of4-mercapto-1-(4-phenoxymethylbenzyl)pyrrolidin-2-one as a white powder.

[1334]¹H-NMR (300 MHz, CDCl₃)

[1335] δ: 7.42 (2H, d, J=7.9 Hz), 7.24-7.33 (4H, m), 6.97 (3H, n), 5.05(2H, s), 4.50 (1H, d, J=14.9 Hz), 4.45 (1H, d, J=14.9 Hz), 3.64 (1H, dd,J=10.2, 7.2 Hz), 3.53 (1H, m), 3.16 (1H, dd, J=10.2, 5.1 Hz), 2.92 (1H,dd, J=17.2, 8.1 Hz), 2.43 (1H, dd, J=17.2, 6.2 Hz), 1.86 (1H, d, J=6.8Hz)

Example 165 4-Acetylthio-1-(4-benzyloxybenzyl)pyrrolidin-2-one

[1336] (1) 4.96 g (40.0 mmol) of 4-hydroxybenzylalcohol was dissolved in100 ml of N,N-dimethylformamide, treated with 5.52 g (40.0 mmol) ofpotassium carbonate and 4.76 ml (40.0 mmol) of benzyl bromide, andstirred at room temperature for 14 hours. The reaction mixture wasconcentrated under reduced pressure, treated with in ethyl acetate,washed twice with water and once with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel, andthe fraction eluted with hexane:ethyl acetate (60:40) was collected andconcentrated under reduced pressure and precipitated from hexane-ethylacetate to obtain 3.92 g (yield: 46%) of 4-benzyloxybenzylalcohol as awhite powder.

[1337]¹H-NMR (300 MHz, CDCl₃)

[1338] δ: 7.26-7.46 (7H, m), 6.97 (2H, d, J=8.3 Hz), 5.07 (2H, s), 4.62(2H, s)

[1339] (2) 2.00 g (9.33 mmol) of 4-benzyloxybenzylalcohol, 755 μl (9.33mmol) of pyridine and 749 μl (10.3 mmol) of thionyl chloride wereprocessed similarly to Example 159, 2.17 g (quantitative yield) of4-benzyloxybenzyl chloride was obtained as a colorless oil.

[1340]¹H-NMR (300 MHz, CDCl₃)

[1341] δ: 7.28-7.45 (7H, m), 6.95 (2H, d, J=8.3 Hz), 5.07 (2H, s), 4.56(2H, s)

[1342] (3) Similarly to Example 30 and starting from 1.40 g (6.00 mmol)of 4-benzyloxybenzyl chloride, 1.04 g (6.00 mmol) of4-trimethylsilyloxypyrrolidin-2-one and 396 mg (7.06 mmol) of powderedpotassium hydroxide, 420 mg (yield: 24%) of4-hydroxy-1-(4-benzyloxybenzyl)pyrrolidin-2-one was obtained as a whitepowder.

[1343] Elemental analysis (%): C₁₈H₁₉NO₃ 0.1H₂O

[1344] Calcd.: C, 72.27; H, 6.47; N, 4.68

[1345] Found: C, 72.22; H, 6.23; N, 4.54

[1346] (4) Starting from 370 mg (1.24 mmol) of4-hydroxy-1-(4-benzyloxybenzyl)pyrrolidin-2-one, 346 μl (2.48 mmol) oftriethylamine and 192 μl (2.48 mmol) of methanesulfonyl chloride, 348 mg(yield: 75%) of4-methanesulfonyloxy-1-(4-benzyloxybenzyl)pyrrolidin-2-one was obtainedas a white powder.

[1347] Elemental analysis (%): C₁₉H₂₁NO₅S

[1348] Calcd.: C, 60.78; H, 5.64; N, 3.73

[1349] Found: C, 60.58; H, 5.77; N, 3.58

[1350] (5) Starting from 298 mg (0.794 mmol) of4-methanesulfonyloxy-1-(4-benzyloxybenzyl)pyrrolidin-2one and 181 mg(1.59 mmol) of potassium thioacetate, 171 mg (yield: 61%) of4-acetylthio-1-(4-benzyloxybenzyl)pyrrolidin-2-one as a white powder.

[1351]¹H-NMR (300 MHz, CDCl₃)

[1352] δ: 7.29-7.46 (5H, m), 7.15 (2H, d, 3=8.5 Hz), 6.94 (2H, d, J=8.5Hz), 5.05 (2H, s), 4.42 (1H, d, J=14.5 Hz), 4.36 (1H, d, J=14.5 Hz),4.03 (1H, m), 3.72 (1H, dd, J=10.6, 7.5 Hz), 3.14 (1H, dd, J=10.6, 4.9Hz), 2.91 (1H, dd, J=17.3, 9.0 Hz), 2.41 (1H, dd, J=17.3, 6.0 Hz), 2.30(3H, s)

Example 166 4-Mercapto-1-(4-benzyloxybenzyl)pyrrolidin-2-one

[1353] 100 mg (0.281 mmol) of4-acetylthio-1-(4-benzyloxybenzyl)pyrrolidin-2-one obtained in Example165 was processed similarly to Example 164 to obtain 46.1 mg (yield:52%) of 4-mercapto-1-(4-benzyloxybenzyl)pyrrolidin-2-one as a whitepowder.

[1354]¹H-NMR (300 MHz, CDCl₃)

[1355] δ: 7.29-7.46 (5H, m), 7.17 (2H, d, J=8.5 Hz), 6.94 (2H, d, J=8.5Hz), 5.05 (2H, s), 4.43 (1H, d, J=14.5 Hz), 4.38 (1H, d, J=14.5 Hz),3.62 (1H, dd, J=10.0, 7.4 Hz), 3.51 (1H, m), 3.13 (1H, dd, J=10.2, 5.1Hz), 2.91 (1H, dd, J=17.2, 8.1 Hz), 2.41 (1H, dd, J=17.2, 6.2 Hz), 1.84(1H, d, J=6.8 Hz)

Example 167 4-Acetylthio-1-(4-phenethylbenzyl)pyrrolidin-2-one

[1356] (1) 4.75 g (22.8 mmol) of trans-4-stilbenecarboxaldehyde wasdissolved in a solvent mixture of 100 ml of methanol and 100 ml oftetrahydrofuran, treated with 450 mg of 10% Pd/C, and stirred underhydrogen atmosphere at room temperature for 3 hours. The catalyst wasfiltered off, and the mixture was concentrated under reduced pressure,dissolved in 40 ml of methanol, treated with 431 mg (11.4 mmol) ofsodium borohydride, and stirred at room temperature for 0.5 hour. Thereaction mixture was adjusted at pH 3.0, concentrated under reducedpressure and extracted twice with ethyl acetate, and the ethyl acetatelayer was washed twice with water and once with saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was subjected to column chromatography on silicagel, and the fraction eluted with hexane:ethyl acetate (70:30) wascollected and concentrated under reduced pressure to obtain 4.34 g(yield: 90%) of 4-phenethylbenzylalcohol as a white powder.

[1357]¹H-NMR (300 MHz, CDCl₃)

[1358] δ 7.24-7.31 (4H, m), 7.19 (5H, m), 4.66 (2H, s), 2.92 (4H, s)

[1359] (2) 2.00 g (9.42 mmol) of 4-phenethylbenzylalchol, 762 μl (9.42mmol) of pyridine and 759 μl (10.4 mmol) of thionyl chloride wereprocessed similarly to Example 159, 2.24 g (quantitative yield) of4-phenethylbenzyl chloride was obtained as a colorless oil.

[1360]¹H-NMR (300 MHz, CDCl₃)

[1361] δ: 7.28 (4H, m), 7.18 (5H, m), 4.57 (2H, s), 2.91 (4H, s)

[1362] (3) Similarly to Example 30 and starting from 1.38 g (6.00 mmol)of 4-phenethylbenzyl chloride, 1.04 g (6.00 mmol) of4-trimethylsilyloxypyrrolidin-2-one and 396 mg (7.06 mmol) of powderedpotassium hydroxide, 730 mg (yield: 41%) of4-hydroxy-1-(4-phenethylbenzyl)pyrrolidin-2-one was obtained as a whitepowder.

[1363] Elemental analysis (%): C₁₉H₂₁NO₂

[1364] Calcd.: C, 77.26; H, 7.17; N, 4.74

[1365] Found: C, 77.30; H, 7.05; N, 4.65

[1366] (4) Starting from 600 mg (2.03 mmol) of4-hydroxy-1-(4-phenethylbenzyl)pyrrolidin-2-one, 566 μl (4.06 mmol) oftriethylamine and 314 μl (4.06 mmol) of methanesulfonyl chloride, 542 mg(yield: 72%) of4-methanesulfonyloxy-1-(4-phenethylbenzyl)pyrrolidin-2-one was obtainedas a white powder.

[1367] Elemental analysis (%): C₂₀H₂₃NO₄S

[1368] Calcd.: C, 64.32; H, 6.21; N, 3.75

[1369] Found: C, 64.38; H, 6.12; N, 3.77

[1370] (5) Starting from 500 mg (1.34 mmol) of4-methanesulfonyloxy-1-(4-phenethylbenzyl)pyrrolidin-2one and 306 mg(2.68 mmol) of potassium thioacetate, 339 mg (yield: 72%) of4-acetylthio-1-(4-phenethylbenzyl)pyrrolidin-2-one was obtained as awhite powder.

[1371] Elemental analysis (%): C₂₁H₂₃NO₂S

[1372] Calcd.: C, 71.35; H, 6.56; N, 3.96

[1373] Found: C, 71.53; H, 6.37; N, 3.95

Example 168 4-Mercapto-1-(4-phenethylbenzyl)pyrrolidin-2-one

[1374] 200-mg (0.566 mmol) of4-acetylthio-1-(4-phenethylbenzyl)pyrrolidin-2-one obtained in Example167 was processed similarly to Example 31 to obtain 154 mg (yield: 87%)of 4-mercapto-1-(4-phenethylbenzyl)pyrrolidin-2-one as a white powder

[1375]¹H-NMR (300 MHz, CDCl₃)

[1376] δ: 7.24-7.31 (3H, m), 7.13-7.23 (6H, m), 4.47 (1H, d, J=14.7 Hz),4.40 (1H, d, J=14.7 Hz), 3.62 (1H, dd, J=9.8, 7.2 Hz), 3.52 (1H, m),3.14 (1H, dd, J=9.8, 4.9 Hz), 2.92 (1H, dd, J=17.0, 8.3 Hz), 2.91 (4H,s), 2.42 (1H, dd, J=17.0, 6.2 Hz), 1.85 (1H, d, J=6.8 Hz)

Example 169 S-[5-Oxo-1-(4-phenoxyphenethyl)-3-pyrrolidinyl]ethanethioate

[1377] 1.3 ml (6.64 mmol) of 4-phenoxyphenethylamine was added to asolution of 1.0 g (6.32 mmol) of O-acetylmalic anhydride in 6.5 ml ofTHF and the mixture was stirred for 1.3 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in 5 ml of acetylchloride, and stirred at 60° C. for 12 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith water, and then twice with a saturated aqueous solution of sodiumhydrogen carbonate and then with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was precipitated from ethyl acetate (yield: 75%) to obtain1.3 g (3.68 mmol) of 2,5-dioxo-1-(4-phenoxyphenethyl)-3-pyrrolidinylacetate, which was then dissolved in a solvent mixture of 6.5 ml ofethanol and 13 ml of THP, and treated with 696 mg (18.40 mmol) of sodiumborohydride at −18° C. and stirred at −18 to −9° C. for 5 hours. Thereaction mixture was partitioned between a saturated aqueous solution ofsodium hydrogen carbonate and ethyl acetate, and the ethyl acetate layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wasdissolved in 13 ml of trifluoroacetic acid, treated with 705 μl (4.42mmol) of triethylsilane, and stirred at room temperature for 30 minutes.The reaction mixture was concentrated under reduced pressure, dissolvedin ethyl acetate, washed twice with a saturated aqueous solution ofsodium hydrogen carbonate and then with saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was purified by column chromatography on silica gel, and thefraction eluted with n-hexane:ethyl acetate (3:2 to 1:1) wasconcentrated to obtain (2 steps, yield: 71%) 1.48 g (4.36 mmol) of5-oxo-1-(4-phenoxyphenethyl)-3-pyrrolidinyl acetate, which was thendissolved in a solution prepared by adding 62 ml (87 mmol) of acetylchloride dropwise to 10 ml of ethanol, and stirred at 50° C. for 1.5hours. The reaction mixture was concentrated under reduced pressure andprecipitated from ethyl acetate to obtain (yield: 80%) 995 mg (3.35mmol) of 4-hydroxy-1-(4-phenoxyphenethyl)-2-pyrrolidinone, which wasthen dissolved in 10 ml of chloroform together with 363 μl (4.69 mmol)of methanesulfonyl chloride, and then treated dropwise with a solutionof 654 μl (4.69 mmol) of triethylamine in 5 ml of chloroform at 0° C.over a period of 5 minutes. After completion of the addition, themixture was stirred at 0° C. for 10 minutes. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedtwice with water and then with saturated brine, and dried over anhydroussodium sulfate. The mixture was concentrated under reduced pressure toobtain 500 mg (1.33 mmol) of 5-oxo-1-(4-phenoxyphenethyl)-3-pyrrolidinylmethanesulfonate, which was then dissolved in a solvent mixture of 10 mlof DMF and 10 ml of ethanol, treated with 304 mg (2.66 mmol) ofpotassium thioacetate, and stirred at 90° C. for 4 hours. After a halfof the solvent was distilled off, the reaction mixture was treated withethyl acetate, washed 5 times with water and then with saturated brine,and dried over anhydrous sodium sulfate. After concentrating underreduced pressure, the residue was purified by column chromatography onsilica gel, and the fraction eluted with n-hexane:ethyl acetate (2:1)was concentrated to obtain 404 mg (yield: 85%) of the title compound asa brown oil.

[1378] Elemental analysis (%): C₂₀H₂₁NO₃S 0.25H₂O

[1379] Calcd.: C, 66.73; H, 6.02; N, 3.89

[1380] Found: C, 66.79; H, 5.98; N, 3.76

Example 170 1-(4-Phenoxyphenethyl)-4-sulfanyl-2-pyrrolidinone

[1381] 91 mg (0.26 mmol) ofS-[5-oxo-1-(4-phenoxyphenethyl)-3-pyrrolidinyl]ethanethioate obtained inExample 169 was dissolved in a mixture of 1 ml of ethanol and 365 μl(5.14 mmol) of acetyl chloride, and stirred at 50° C. for 1.5 hours, andthe reaction mixture was concentrated under reduced pressure, andpurified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 64 mg (yield: 70%) of the titlecompound as a colorless oil.

[1382]¹H-NM (300 MHz, CDCl₃)

[1383] δ: 7.35-6.93 (9H, m), 3.65-3.41 (4H, m), 3.16 (1H, dd, J=10.0,5.1 Hz), 2.85-2.78 (3H, m), 2.32 (1H, dd, J=16.9, 6.2 Hz), 1.84. (1H, d,J=7.0 Hz).

Example 171 4-Acetylthio-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one

[1384] (1) 324 mg (1.08 mmol) of4-hydroxy-1-(4-phenylthiobenzyl)pyrrolidin-2-one obtained in Example 154was dissolved in a mixture of 7 ml of acetic acid and 2 ml of 30%aqueous hydrogen peroxide, and stirred at room temperature for 1 hour.The reaction mixture was treated with ethyl acetate, washed twice withwater and then with saturated brine, and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wassubjected to column chromatography on silica gel, and the fractioneluted with hexane: acetone (30:70-0:100) was concentrated under reducedpressure to obtain 239 mg (yield: 70%) of4-hydroxy-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one as a colorless oil.

[1385]¹H-NMR (300 MHz, CDCl₃)

[1386] δ: 7.62 (4H, m), 7.46 (3H, m), 7.34 (2H, d, J=8.3 Hz), 4.57 (1H,d, J=15.3 Hz), 4.50 (1H, m), 4.40 (1H, d, J=15.3 Hz), 3.50 (1H, dd,J=10.9, 5.7 Hz), 3.18 (1H, dd, J=10.9, 1.7 Hz), 2.71 (1H, dd, J=17.3,6.4 Hz), 2.42 (1H, dd, J=17.3, 2.5 Hz)

[1387] (2) Starting from 215 mg (0.682 mmol) of4-hydroxy-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one, 286>1 (2.04 mmol)of triethylamine and 158 μl (2.04 mmol) of methanesulfonyl chloride, 198mg (yield: 74%) of4-methanesulfonyloxy-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one wasobtained as a colorless oil.

[1388]¹H-NMR (300 MHz, CDCl₃)

[1389] δ: 7.64 (4H, m), 7.47 (3H, m), 7.33 (2H, d, J=8.3 Hz), 5.28 (1H,m), 4.53 (1H, d, J=17.2 Hz), 4.48 (1H, d, J=17.2 Hz), 3.64 (1H, dd,J=12.1, 5.5 Hz), 3.50 (1H, br, d, J=12.1 Hz), 3.00 (3H, s), 2.87 (1H,dd, J=18.1, 6.9 Hz), 2.71 (1H, dd, J=18.1, 2.3 Hz)

[1390] (3) Starting from 180 mg (0.457 mmol) of4-methanesulfonyloxy-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one and 104mg (0.915 mmol) of potassium thioacetate, 129 mg (yield: 76%) of4-acetylthio-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one was obtained asa colorless oil.

[1391] Elemental analysis (%): C₁₉H₁₉NO₃S₂

[1392] Calcd.: C, 61.10; H, 5.13; N, 3.75

[1393] Found: C, 61.05; H, 5.22; N, 3.83

Example 172 4-Mercapto-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one

[1394] Starting from 60.0 mg (0.161 mmol) of4-acetylthio-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one obtained inExample 171 and 229 μl (3.22 mmol) of acetyl chloride and similarly toExample 126, 17.9 mg (yield: 34%) of4-mercapto-1-(4-phenylsulfinylbenzyl)pyrrolidin-2-one was obtained as acolorless oil.

[1395]¹H-NMR (300 MHz, CDCl₃)

[1396] δ: 7.64 (4H, m), 7.47 (3H, m), 7.35 (2H, d, J=7.9 Hz), 4.51 (1H,d, J=15.1 Hz), 4.43 (1H, d, J=15.1 Hz), 3.63 (1H, dd, J=9.6, 7.5 Hz),3.55 (1H, m), 3.14 (1H, dd, J=9.6, 4.5 Hz), 2.91 (1H, dd, J=17.2, 8.1Hz), 2.41 (1H, dd, J=17.2, 5.9 Hz), 1.86 (1H, d, J=6.8 Hz)

Example 173 4-Acetylthio-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one

[1397] (1) 280 mg (0.935 mmol) of4-hydroxy-1-(4-phenylthiobenzyl)pyrrolidin-2-one obtained in Example 154was dissolved in a mixture of 7 ml of acetic acid and 2 ml of 30%aqueous hydrogen peroxide, and stirred at 70° C. for 1 hour. Thereaction mixture was treated with ethyl acetate, washed twice with waterand then with saturated brine, and dried over anhydrous sodium sulfate.After concentrating under reduced pressure, toluene was added and thenthe mixture was concentrated under reduced pressure again into dryness,and precipitated from ethyl acetate to obtain 310 mg (quantitativeamount) of 4-hydroxy-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one as awhite powder.

[1398] Elemental analysis (%): C₁₇H₁₇NO₄S

[1399] Calcd.: C, 61.61; H, 5.17; N, 4.23

[1400] Found: C, 61.31; H, 4.95; N, 4.21

[1401] (2) Starting from 310 mg (0.935 mmol) of4-hydroxy-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one, 430 μl (3.10 mmol)of triethylamine and 240 μl (3.10 mmol) of methanesulfonyl chloride, 359mg (yield: 94%) of4-methanesulfonyloxy-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one wasobtained as a colorless oil.

[1402] Elemental analysis (%): C₁₈H₁₉NO₆S₂

[1403] Calcd.: C, 52.80; H, 4.68; N, 3.42

[1404] Found: C, 52.82; H, 4.57; N, 3.47

[1405] (3) Starting from 280 mg (0.684 mmol) of4-methanesulfonyloxy-1-(4-1.5 phenylsulfonylbenzyl)pyrrolidin-2-one and156 mg (1.37 mmol) of potassium thioacetate, 175 mg (yield: 66%) of4-acetylthio-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one was obtained asa white powder.

[1406] Elemental analysis (%): C₁₉H₁₉NO₄S₂

[1407] Calcd.: C, 58.59; H, 4.92; N, 3.60

[1408] Found: C, 58.59; H, 4.85; N, 3.68

Example 174 4-Mercapto-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one

[1409] Starting from 90.0 mg (0.231 mmol) of4-acetylthio-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one obtained inExample 173 and 365 μl (5.14 mmol) of acetyl chloride and similarly toExample 126, 61.2 mg (yield: 76%) of4-mercapto-1-(4-phenylsulfonylbenzyl)pyrrolidin-2-one was obtained as awhite powder.

[1410] Elemental analysis (%): C₁₇H₁₇NO₃S₂

[1411] Calcd.: C, 58.77; H, 4.93; N, 4.03

[1412] Found: C, 58.79; H, 4.93; N, 4.03

Example 175 (4S,5S)-4-Acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1413] (1) Similarly to Example 20 and starting from 2.34 g (15.0 mmol)of L-alanine methyl ester hydrochloride, 3.14 ml (22.5 mmol) oftriethylamine and 2.63 ml (15.0 mmol) of 4-phenoxybenzaldehyde, 4.31 g(quantitative yield) of N-(4-phenoxybenzy)-L-alanine methyl ester wasobtained as a colorless oil.

[1414]¹H-NMR (300 MHz, CDCl₃)

[1415] δ: 7.27-7.37 (4H, m), 7.09 (1H, m), 6.98 (4H, m), 3.77 (1H, d,J=12.8 Hz), 3.74 (3H, s), 3.64 (1H, d, J=12.8 Hz), 3.40 (1H, q, J=6.8Hz), 1.33 (3H, d, J=6.8 Hz)

[1416] (2) Starting from 4.21 g (14.8 mmol) ofN-(4-phenoxybenzy)-L-alanine methyl ester, 2.48 ml (17.8 mmol) oftriethylamine and 2.28 ml (17.8 mmol) of ethylmalonyl chloride, 5.11 g(yield: 86%) of N-(ethylmalonyl)-N-(4-phenoxybenzyl)-L-alanine methylester was obtained as a colorless oil.

[1417]¹H-NMR (300 MHz, CDCl₃)

[1418] δ: 7.20-7.40 (4H, m), 7.13 (1H, m), 6.97-7.04 (4H, n), 4.66 (1H,q, J=7.2 Hz), 65 (1H, d, J=17.3 Hz), 4.50 (1H, d, J=17.3 Hz), 4.19 (1H,q; J=7.2 Hz), 3.69 (3H, s), 3.47 (1H, d, J=15.5 Hz), 3.39 (1H, d, J=15.5Hz), 1.41 (3H, d, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz)

[1419] (3) 5.00 g (12.5 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-L-alanine methyl ester and 4.91 ml(12.5 mmol) of a 20% solution of sodium ethoxide in ethanol were treatedand decarboxylated, and then 473 mg (12.5 mmol) of sodium borohydridewas used to obtain 3.61 g (yield: 97%) of(5S)-4-hydroxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1420] Major Peaks:

[1421]¹H-NMR (300 MHz, CDCl₃)

[1422] δ: 7.33 (2H, m), 7.19 (2H, m), 7.10 (1H, m), 6.97-7.03 (4H, m),4.95 (1H, d, J=15.1 Hz), 4.35 (1H, m), 3.97 (1H, d, J=15.1 Hz), 3.60(1H, m), 2.70 (1H, dd, J=17.0, 6.6 Hz), 2.47 (1H, dd, J=17.0, 3.4 Hz),1.22 (3H, d, J=6.8 Hz)

[1423] (4) Starting from 3.50 g (11.8 mmol) of(5S)-4-hydroxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one, 3.28 ml(23.5 mmol) of triethylamine and 1.81 ml (23.5 mmol) of methanesulfonylchloride, 3.87 g (yield: 87%) of(5S)-4-methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-onewas obtained as a colorless oil. This product was subjected tofractional high-pressure liquid chromatography (column: YMC Pack S-363I-15 ODS, Mobile phase: 42% acetonitrile/0.01 M phosphate buffer, pH6.3, flow rate: 20 ml/min, detection: 214 nm), and each of the fractionsof 2 peaks was concentrated and extracted twice with ethyl acetate. Theethyl acetate layer was washed with water and saturated brine, driedover anhydrous sodium sulfate and concentrated to obtain 1.20 g(recovery: 31%) of (4R,5S)-4-methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one asa colorless oil and 2.08 g (recovery: 54%) of (4S,5S)-4-methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one asa white powder.

[1424] (4R,5S)-4-Methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1425]¹H-NMR (300 MHz, CDCl₃)

[1426] δ: 7.34 (2H, m), 7.21 (2H, d, J=8.7 Hz), 7.11 (1H, m), 6.98 (4H,m), 4.97 (1H, d, J=15.1 Hz), 4.90 (1H, m), 3.98 (1H, d, J=15.1 Hz), 3.73(1H, dq, J=1.5, 6.8 Hz), 2.97 (3H, s), 2.95 (1H, dd, J=18.1, 6.8 Hz),2.66 (1H, dd, J=18.1, 2.3 Hz), 1.23 (3H, d, J=6.8 Hz)

[1427] (4S,5S)-4-Methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1428]¹H-NMR (300 MHz, CDCl₃)

[1429] δ: 7.35 (2H, m), 7.18 (2H, d, J=8.3 Hz), 7.12 (1H, m), 7.01 (2H,m), 6.95 (2H, d, J=8.3 Hz), 5.21 (1H, m), 4.98 (1H, d, J=15.1 Hz), 3.96(1H, d, J=15.1 Hz), 3.80 (1H, m), 3.06 (3H, s), 2.83 (1H, dd, J=17.3,6.4 Hz), 2.74 (1H, dd, J=17.3, 4.0 Hz), 1.28 (3H, d, J=6.4 Hz)

[1430] (5) 1.00 g (2.66 mmol) of (4H,5S)-4-methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-onewas dissolved in 30 ml of ethanol, treated with 608 mg (5.33 mmol) ofpotassium thioacetate, and heated under reflux for 13 hours withstirring. The reaction mixture was concentrated, treated with in ethylacetate, washed with water and saturated brine, and dried over anhydroussodium sulfate. After concentrating, the residue was subjected to columnchromatography on silica gel eluting with hexane:ethyl acetate (60:40),concentrated into dryness to obtain 207 mg (yield: 22%) of (4S,5S)-4-acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1431]¹H-NMR (300 MHz, CDCl₃)

[1432] δ: 7.34 (2H, n), 7.20 (2H, d, J=8.3 Hz), 7.11 (1H, m), 7.01 (2H,m), 6.96 (2H, m), 4.93 (1H, d, J=15.1 Hz), 4.18 (1H, m), 3.96 (1H, d,J=15. Hz), 3.84 (1H, m), 2.82 (1H, dd, J=17.0, 8.3 Hz), 2.45 (1H, dd,J=17.0, 9.1 Hz), 2.34 (3H, s), 1.13 (3H, d, J=6.4 Hz)

Example 176 (4S,5S)-4-Mercapto-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1433] 120 mg (0.338 mmol) of (4S,5S)-4-acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one obtainedin Example 175 was processed similarly to Example 31 to obtain 81.2 mg(yield: 77%) of (4S,5S)-4-mercapto-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1434]¹H-NMR (300 MHz, CDCl₃)

[1435] δ: 7.34 (2H, m), 7.20 (2H, d, J=8.3 Hz), 7.11 (1H, m), 7.00 (2H,m), 6.96 (2H, d, J=8.3 Hz), 4.96 (1H, d, J=15.1 Hz), 3.95 (1H, d, J=15.1Hz), 3.65 (1H, m), 3.58 (1H, m), 2.84 (1H, dd, J=17.0, 7.5 Hz), 2.46(1H, dd, J=17.0, 7.7 Hz), 1.52 (1H, d, J=7.5 Hz), 1.23 (3H, d, J=6.4 Hz)

Example 177 (4R,5S)-4-Acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1436] 1.50 g (4.00 mmol) of (4S,5S)-4-methanesulfonyloxy-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 175 and 914 mg (8.00 mmol) of potassium thioacetatewere processed similarly to Example 175 to obtain 596 mg (yield: 42%) of(4R, 5S)-4-acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1437]¹H-NMR (300 MHz, CDCl₃)

[1438] δ: 7.34 (2H, m), 7.19 (2H, d, J=8.3 Hz), 7.11 (1H, m), 7.00 (2H,m), 6.96 (2H, m), 4.95 (1H, d, J=15.1 Hz), 3.95 (1H, d, J=15.1 Hz), 3.68(1H, m), 3.39 (1H, m), 3.02 (1H, dd, J=17.7, 8.9 Hz), 2.39 (1H dd,J=17.7, 5.7 Hz), 2.31 (3H, s), 1.26 (3H, d, J=6.4 Hz)

Example 178 (4R,5S)-4-Mercapto-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1439] 301 mg (0.847 mmol) of (4R,5S)-4-acetylthio-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one obtainedin Example 177 was processed similarly to Example 31 to obtain 210 mg(yield: 79%) of (4R,5S)-4-mercapto-5-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1440]¹H-NMR (300 MHz, CDCl₃)

[1441] δ: 7.34 (2H, m), 7.21 (2H, d, J=8.7 Hz), 7.11 (1H, m), 7.00 (2H,m), 96 (2H, d, J=8.7 Hz), 4.96 (1H, d, J=15.1 Hz), 3.96 (1H, d, J=]5.1Hz), 3.33 (1H, m), 3.03 (1H, m), 2.95 (1H, m), 2.39 (1H, dd, J=16.2, 6.8Hz), 1.75 (1H, d, J=6.8 Hz), 1.25 (3H, d, J=6.4 Hz)

Example 179trans-4-Acetylthio-5-isobutyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1442] (1) Similarly to Example 20 and starting from 6.56 g (50.0 mmol)of D,L-leucine, 50 ml of methanol and 13.0 ml (180 mmol) of thionylchloride, 8.93 g (yield: 98%) of D,L-leucine methyl ester hydrochloridewas obtained as a white powder.

[1443]¹H-NMR (300 MHz, D₂O)

[1444] δ: 4.17 (1H, t, J=6.8 Hz), 3.87 (3H, s), 1.90 (1H, m), 1.78 (2H,m), 00 (3H, d, J=6.0 Hz), 0.99 (3H, d, J=6.0 Hz)

[1445] (2) Starting from 2.73 g (15.0 mmol) of D,L-leucine methyl esterhydrochloride, 3.14 ml (22.5 mmol) of triethylamine, 2.63 ml (15.0 mmol)of 4-phenoxybenzaldehyde and 420 mg (11.1 mmol) of sodium borohydride,4.34 g (yield: 88%) of N-(4-phenoxybenzyl)-D,L-leucine methyl ester wasobtained as a colorless oil.

[1446]¹H-NM (300 MHz, CDCl₃)

[1447] δ: 7.30 (4H, m), 7.08 (1H, m), 6.97 (4H, m), 3.78 (1H, d, J=12.8Hz), 3.73 (3H, s), 3.58 (1H, d, J=12.8 Hz), 3.31 (1H, t, J=7.2 Hz), 1.78(1H, m), 1.48 (2H, t, J=7.2 Hz), 0.92 (3H, d, J=6.8 Hz), 0.85 (3H, d,J=6.4 Hz)

[1448] (3) Starting from 4.34 g (13.3 mmol) ofN-(4-phenoxybenzyl)-D,L-leucine methyl ester, 2.22 ml (16.0 mmol) oftriethylamine and 2.05 ml (16.0 mmol) of ethylmalonyl chloride, 5.24 g(yield: 89%) of N-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-leucine methylester was obtained as a colorless oil.

[1449] Major Peaks:

[1450]¹H-NMR (300 MHz, CDCl₃)

[1451] δ: 7.21-7.38 (4H, m), 7.12 (1H, m), 6.91-7.03 (4H, m), 4.86 (1H,m), 4.63 (1H, d, J=17.3 Hz), 4.50 (1H, d, J=17.3 Hz), 4.19 (2H, q, J=7.2Hz), 3.62 (3H, s), 3.47 (1H, d, J=15.5 Hz), 3.42 (1H, d, J=15.5 Hz),1.88 (1H, m), 1.60 (2H, m), 1.28 (3H, t, J=7.2 Hz), 0.91 (3H, d, J=6.4Hz), 0.84 (3H, d, J=6.0 Hz)

[1452] (4) 5.24 g (11.9 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-leucine methyl ester wastreated with 4.66 ml (11.9 mmol) of a 20% solution of sodium ethoxide inethanol, decarboxylated and reacted with 450 mg (11.9 mmol) of sodiumborohydride to obtain 3.52 g (yield: 87%) of4-hydroxy-5-isobutyl-1-(4-phenoxybenzyl)pyrrolidine-2-one as a colorlessoil. Major Peaks:

[1453]¹H-NM (300 MHz, CDCl₃)

[1454] δ: 7.33 (2H, m), 7.18 (2H, d, J=8.7 Hz), 7.10 (1H, m), 6.97 (4H,m), 4.96 (1H, d, J=15.3 Hz), 4.37 (1H, m), 3.97 (1H, d, J=15.3 Hz), 3.49(1H, m), 2.67 (1H, dd, J=17.0, 5.9 Hz), 2.47 (1H, dd, J=17.0, 1.9 Hz),1.70 (2H, m), 1.40 (1H, m), 0.94 (3H, d, J=6.4 Hz), 0.81 (3H, d, J=6.4Hz)

[1455] (5) 3.30 g (9.72 mmol) of4-hydroxy-5-isobutyl-1-(4-phenoxybenzyl)pyrrolidine-2-one was reactedwith 2.71 ml (19.4 mmol) of triethylamine and 1.50 ml (19.4 mmol) ofmethanesulfonyl chloride, and subjected similarly to Example 175 tofractional high pressure liquid chromatography to obtain 2.63 g (yield:65%) ofcis-5-isobutyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a white powder.

[1456]¹H-NMR (300 MHz, CDCl₃)

[1457] δ: 7.34 (2H, m), 7.17 (2H, d, J=8.7 Hz), 7.11 (1H, m), 6.98 (4H,m), 5.26 (1H, m), 5.02 (1H, d, J=5.3 Hz), 3.96 (1H, d, =15.3 Hz), 3.68(1H, m), 3.06 (3H, s), 2.82 (1H, dd, J=17.9, 2.8 Hz), 2.75 (1H, dd,J=17.9, 5.5 Hz), 1.70 (1H, m), 1.67 (1H, m), 1.47 (1H, m), 0.94 (3H, d,J=6.4 Hz), 0.79 (3H, d, J=6.4 Hz)

[1458] (6) Starting from 1.00 g (2.40 mmol) ofcis-5-isobutyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneand 548 mg (4.80 mmol) of potassium thioacetate, 227 mg (yield: 24%) oftrans-4-acetylthio-5-isobutyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1459]¹H-NIR (300 MHz, CDCl₃)

[1460] δ: 7.34 (2H, m), 7.19 (2H, d, J=8.7 Hz), 7.11 (1H, m), 6.99 (4H,m), 5.02 (1H, d, J=15.3 Hz), 3.86 (1H, d, J=15.3 Hz), 3.81 (1H, m), 3.30(1H, m), 3.09 (1H, dd, J=17.7, 7.9 Hz), 2.37 (1H, dd, J=17.7, 2.3 Hz),2.29 (3H, s), 1.77 (1H, m), 1.42 (2H, m), 0.92 (3H, d, J=6.8 Hz), 0.80(3H, d, J=6.8 Hz)

Example 180trans-5-Isobutyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1461] 227 mg (0.571 mmol) oftrans-4-acetylthio-5-isobutyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 179 was processed similarly to Example 31 to obtain165 mg (yield: 81%) oftrans-5-isobutyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1462]¹H-NMR (300 MHz, CDCl₃)

[1463] δ: 7.34 (2H, m), 7.24 (2H, d, J=8.3 Hz), 7.11 (1H, m), 6.99 (4H,m), 5.03 (1H, d, J=15.1 Hz), 3.88 (1H, d, J=15.1 Hz), 3.29 (1H, m), 3.23(1H, m), 3.03 (1H, dd, J=17.3, 7.9 Hz), 2.38 (1H, dd, J=17.3, 2.6 Hz),1.78 (1H, d, J=6.8 Hz), 1.68 (1H, m), 1.48 (1H, m), 1.28 (1H, m), 0.93(3H, d, J=6.8 Hz), 0.85 (3H, d, J=6.4 Hz)

Example 181trans-4-Acetylthio-5-benzyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1464] (1) Similarly to Example 20 and starting from 8.26 g (50.0 mmol)of D,L-phenylalanine, 50 ml of methanol and 13.0 ml (180 mmol) ofthionyl chloride, 10.6 g (yield: 98%) of D,L-phenylalanine methyl esterhydrochloride was obtained as a white powder.

[1465]¹H-NMR (300 MHz, D₂O)

[1466] δ: 7.45 (3H, m), 7.34 (2H, m), 4.46 (1H, m), 3.87 (3H, s), 3.39(1H, dd, J=14.3, 5.9 Hz), 3.27 (1H, dd, J=14.3, 7.5 Hz)

[1467] (2) Starting from 3.24 g (15.0 mmol) of D,L-phenylalanine methylester hydrochloride, 3.14 ml (22.5 mmol) of triethylamine, 2.63 ml (15.0mmol) of 4-phenoxybenzaldehyde and 496 mg (13.1 mmol) of sodiumborohydride, 4.05 g (yield: 75%) ofN-(4-phenoxybenzyl)-D,L-phenylalanine methyl ester was obtained as acolorless oil.

[1468]¹H-NMR (300 MHz, CDCl₃)

[1469] δ: 7.21-7.36 (5H, m), 7.14-7.20 (4H, m), 7.09 (1H, m), 6.99 (2H,m), 6.92 (2H, d, J=8.3 Hz), 3.78 (1H, d, J=12.8 Hz), 3.66 (3H, s), 3.60(1H, d, J=12.8 Hz), 3.54 (1H, t, J=6.8 Hz), 2.99 (1H, dd, J=13.6, 6.4Hz), 2.94 (1H, dd, J=13.6, 7.5 Hz)

[1470] (3) Starting from 4.05 g (11.2 mmol) ofN-(4-phenoxybenzyl)-D,L-phenylalanine methyl ester, 1.87 ml (13.4 mmol)of triethylamine and 1.72 ml (13.4 mmol) of ethylmalonyl chloride, 5.34g (yield: 100%) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-phenylalanine methyl ester wasobtained as a colorless oil.

[1471] Major Peaks:

[1472]¹H-NMR (300 MHz, CDCl₃)

[1473] δ: 7.23-7.38 (6H, m), 7.06-7.19 (4H, m), 6.99 (2H, m), 6.90 (2H,d, J=8.7 Hz), 4.41 (1H, d, J=16.8 Hz), 4.28 (1H, dd, J=9.4, 5.7 Hz),4.21 (2H, q, J=7.2 Hz), 3.83 (1H, d, J=16.8 Hz), 3.66 (3H, s), 3.46 (1H,d, J=14.9 Hz), 3.38 (1H, d, J=14.9 Hz), 3.36 (1H, m), 3.25 (1H, m), 1.29(3H, t, J=7.2 Hz)

[1474] (4) 5.34 g (11.2 mmol) ofN-(ethylmalonyl)-N-(4-phenoxybenzyl)-D,L-phenylalanine methyl ester wastreated with 4.39 ml (11.2 mmol) of a 20% solution of sodium ethoxide inethanol, decarboxylated and reacted with 424 mg (11.2 mmol) of sodiumborohydride to obtain 3.93 g (yield: 94%) of5-benzyl-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidine-2-one as a colorlessoil.

[1475] Major Peaks:

[1476]¹H-NMR (300 MHz, CDCl₃)

[1477] δ: 7.20-7.38 (5H, m), 7.08-7.19 (5H, m), 7.01 (2H, m), 6.96 (2H,d, J=8.7 Hz), 5.02 (1H, d, J=15.1 Hz), 4.22 (1H, m), 3.93 (1H, d, J=15.1Hz), 3.73 (1H, dt, J=5.3, 7.5 Hz), 3.00 (2H, d, J=7.5 Hz), 2.63 (1H, dd,J=17.0, 6.4 Hz), 2.44 (1H, dd, J=17.0, 3.4 Hz); 1.84 (1H, d, J=4.5 Hz)

[1478] (5) 3.70 g (9.91 mmol) of5-benzyl-4-hydroxy-1-(4-phenoxybenzyl)pyrrolidine-2-one was reacted with2.76 ml (19.8 mmol) of triethylamine and 1.53 ml (19.8 mmol) ofmethanesulfonyl chloride, and subjected similarly to Example 175 tofractional high pressure liquid chromatography to obtain 1.65 g (yield:37%) ofcis-5-benzyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-one asa white powder.

[1479]¹H-NMR (300 MHz, CDCl₃)

[1480] δ: 7.22-7.39 (5H, m), 7.14 (3H, m), 7.02 (4H, m), 6.94 (2H, d,J=8.7 Hz), 5.09 (1H, m), 5.06 (1H, d, J=15.1 Hz), 4.01 (1H, m), 3.75(1H, d, J=15.1 Hz), 3.05 (2H, d, J=6.8 Hz), 2.87 (3H, s), 2.74 (2H, d,J=6.0 Hz)

[1481] (6) Starting from 1.35 g (2.99 mmol) ofcis-5-benzyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneand 683 mg (5.98 mmol) of potassium thioacetate, 327 mg (yield: 25%) oftrans-4-acetylthio-5-benzyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1482] Elemental analysis (%): C₂₆H₂₅NO₃S·0.2H₂O

[1483] Calcd.: C, 71.76; H, 5.88; N, 3.22

[1484] Found: C, 71.71; H, 6.02; N, 2.97

Example 182trans-5-Benzyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1485] 185 mg (0.429 mmol) oftrans-4-acetylthio-5-benzyl-1-(4-phenoxybenzyl)pyrrolidin-2-one obtainedin Example 181 was processed similarly to Example 31 to obtain 135 mg(yield: 81%) oftrans-5-benzyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1486] Elemental analysis (%): C₂₄H₂₃NO₂S·0.2H₂O

[1487] Calcd.: C, 73.33;H, 6.00; N, 3.56

[1488] Found: C, 73.41; H, 6.16; N, 3.56

Example 183trans-4-Acetylthio-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1489] 122 mg (1.43 mmol) of propyl isocyanate was dissolved in 20 ml ofchloroform, 0.36 ml (1.43 mmol) of a 4N solution of hydrogen chloride inethyl acetate was added, and then 280 mg (0.72 mmol) ofcis-5-hydroxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 20 was added with stirring. After stirring at roomtemperature overnight, the reaction mixture was subjected to columnchromatography on silica gel eluting with methanol:chloroform (3:97) toobtain 320 mg (yield: 94%) ofcis-4-methanesulfonyloxy-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1490] 300 mg (0.63 mmol) of the cis-mesylate thus obtained wasdissolved in 15 ml of ethanol, treated with 360 mg (3.15 mmol) ofpotassium thioacetate and then stirred at 90° C. for 3 hours. Thereaction mixture was concentrated, and the residue was extracted withethyl acetate and water, and the ethyl acetate layer was washed withwater and concentrated, and the residue was subjected to columnchromatography on silica gel eluting with ethyl acetate: n-hexane(30:70) to obtain 31 mg (yield: 22%) oftrans-4-acetylthio-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1491]¹H-NMR (200 MHz, CDCl₃)

[1492] d: 7.40-6.90 (1H, m), 5.01 (1H, d, J=15.7 Hz), 4.87-4.65 (1H, m),4.42-4.32 (1H, m) 4.21-3.95 (3H, m), 3.52-3.45 (1H, m), 3.20-3.08 (2H,m), 3.05 (1H, dd, J=8.9, 17.8 Hz) 2.37 (1H, dd, J=4.0, 22.0 Hz), 2.30(3H, s), 1.60-1.45 (2H, m), 0.92 (3H, t, J=7.5 Hz).

Example 184trans-4-Mercapto-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1493] 57 mg (0.13 mmol) oftrans-4-acetylthio-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 183 was dissolved in 5 ml of methanol, treated with24 μl (0.13 mmol) of a 28% solution of sodium methoxide in methanol andstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated, and the residue was extracted with ethyl acetate anddilute hydrochloric acid, and the ethyl acetate layer was washed withwater and concentrated, and the residue was subjected to columnchromatography on silica gel eluting with ethyl acetate: n-hexane(30:70) to obtain 23 mg (yield: 44%) oftrans-4-mercapto-5-propylaminocarbonyloxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1494]¹H-NMR (200 MHz, CDCl₃)

[1495] d: 7.40-6.90 (9H, m), 5.02 (1Hz d, J=15.0 Hz), 4.87-4.65 (1H, m),4.30-4.10 (2H, m) 3.99 (1H, d, J=15.0 Hz), 3.51-3.35 (2H, m), 3.19-3.08(2H, m), 3.00 (1H, dd, J=8.3, 16.0 Hz), 2.39 (1H, dd, J=5.2, 16.0 Hz),1.87 (1H, d, J=6.9 Hz), 1.60-1.43 (2H, m), 0.92 (3H, t, J=7.4 Hz)

Example 185

[1496]trans-4-Acetylthio-5-(tetrahydro-2H-pyran-2-yl)oxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1497] 200 mg (0.51 mmol) ofcis-5-hydroxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 20 was dissolved in 5 ml of chloroform, treated with51 mg (0.61 mmol) of dihydropyrane and 1 drop of conc. hydrochloric acidand stirred at room temperature for 3 hours.

[1498] The reaction mixture was extracted with a saturated aqueoussolution of sodium hydrogen sulfate, and the chloroform layer was washedwith water and concentrated, and the residue was subjected to columnchromatography on silica gel eluting with chloroform to obtain 210 mg(yield: 87%) of 5-(tetrahydro-2H-pyran-2-yl)oxymethyl product as acolorless oil.

[1499] 200 mg (0.42 mmol) of 5-(tetrahydro-2H-pyran-2-yl)oxymethylproduct thus obtained and 240 mg (2.10 mmol) of potassium thioacetatewere subjected to a method similar to that in Example 183 to obtain 40mg (yield: 21%) oftrans-4-acetylthio-5-tetrahydro-2H-pyran-2-yl)oxymethyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1500]¹H-NMR (200 MHz, CDCl₃)

[1501] d: 7.40-6.90 (18H, m), 5.09 (1H, d, J=15.2 Hz), 4.83 (1H, d,J=15.1 Hz), 4.66-4.63 (1H, m), 4.39-4.35 (1H, m), 4.19 (1H, d, J=15.0Hz), 4.05-3.40 (12H, n), 3.21-3.06 (2H, m), 2.40-2.39 (2H, m), 2.30 (3H,s), 2.29 (3H, s), 1.80-1.45 (12H, m).

Example 186trans-4-Acetylthio-5-ethoxycarbonylmethylaminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1502] 500 mg (1.28 mmol) ofcis-5-hydroxymethyl-4-methanesulfonyloxy-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 20 was dissolved in 20 ml of acetone, treateddropwise with Jones reagent with cooling on ice and stirring until theorange color of the reaction mixture was observed stably, and then thestirring was continued further for 2 hours with cooling on ice. 1 ml of2-propanol was added, and the mixture was extracted with ethyl acetateand water. The ethyl acetate layer was washed with water andconcentrated, and the residue was treated with ethyl acetate andn-hexane to effect a precipitation, whereby obtaining 450 mg (yield:87%) of a 5-carboxylic acid product as a white powder.

[1503] 300 mg (0.74 mmol) of the carboxylic acid product thus obtainedwas dissolved in 15 ml of N,N-dimethylformamide, and treated with 153 mg(0.80 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 108 mg(0.80 mmol) of hydroxybenzotriazole and stirred at room temperature for15 minutes. To this reaction mixture, a solution of 112 mg (0.80 mmol)of glycine ethyl ester hydrochloride and 81 mg (0.80 mmol) oftriethylamine dissolved in 3 ml of dimethylformamide was added dropwiseat room temperature, and the mixture was stirred for 3 hours. Thereaction mixture was extracted with ethyl acetate and dilutedhydrochloric acid, and the ethyl acetate layer was washed with water andconcentrated, and the residue was subjected to column chromatography onsilica gel eluting with chloroform:methanol (98:2) to obtain 160 mg(yield: 44%) of a 5-ethoxycarbonylmehtylaminocarbonyl product as acolorless oil.

[1504] 170 mg (0.35 mmol) of the 5-ethoxycarbonylmehtylaminocarbonylproduct thus obtained and 198 mg (1.73 mmol) of potassium thioacetatewere subjected to a method similar to that in Example 183 to obtain 41mg (yield: 25%) oftrans-4-acetylthio-5-ethoxycarbonylmethylaminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1505]¹H-NMR (200 MHz, CDCl₃)

[1506] d: 7.40-6.90 (10H, m), 5.17 (1H, d, J=15.1 Hz), 4.26-3.80 (5H,m), 4.24 (2H, q, J=7.2 Hz), 3.05 (1H, dd, J=8.1, 18.0 Hz), 2.34 (1H, dd,J=1.5, 18.0 Hz), 2.33 (3H, s), 1.30 (3H, t, J=7.2 Hz)

Example 187trans-5-Aminocarbonyl-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1507] Similarly to Example 186and starting from 578 mg (1.43 mmol) of acarboxylic acid product and conc. aqueous ammonia, 220 mg (yield: 46%)of an amide product was obtained. 220 mg (0.54 mmol) of the amideproduct thus obtained and 310 mg (2.72 mmol) of potassium thioacetatewere then used to produce 28 mg (yield: 14%) oftrans-5-aminocarbonyl-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a white powder.

[1508]¹H-NMR (200 MHz, CDCl₃)

[1509] d: 7.40-6.90 (9H, n), 6.73 (1H, brs), 5.66 (1H, brs), 5.19 (1H,d, J=15.3 Hz), 3.98 (1H, d, J=8.9 Hz), 3.85 (1H, d, J=15.4 Hz), 3.77(1H, s), 3.05 (1H, dd, J=9.0, 17.8 Hz), 2.35 (1H, dd, J=1.4, 18.0 Hz),2.33 (3H, s)

Example 188trans-5-Aminocarbonyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1510] 57 mg (0.13 mmol) oftrans-5-aminocarbonyl-4-acetylthio-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 187 was subjected to a method similar to that inExample 184 to obtain 23 mg (yield: 44%) oftrans-5-aminocarbonyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one asa colorless oil.

[1511]¹H-NMR (200 MHz, CDCl₃)

[1512] d: 7.40-6.90 (9H, m), 5.84 (111 brs), 5.68 (1H, brs), 5.14 (1H,d, J=14.8 Hz), 3.88 (1H, d, J=14.7 Hz), 3.72 (1H, d, J=4.1 Hz),3.62-3.48 (1H, m), 3.07 (1H, dd, J=8.2, 18.0), 2.39 (1H, dd, J=5.0, 18.0Hz), 2.04 (1H, d, J=7.2 Hz)

Example 189trans-4-Acetylthio-5-(2-hydroxyethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1513] Similarly to Example 186 and starting from 700 mg (1.73 mmol) ofa carboxylic acid product and 2-aminoethanol, 180 mg (yield: 23%) of anamide product was obtained. 160 mg (0.36 mmol) of the amide product thusobtained and 163 mg (1.43 mmol) of potassium thioacetate were then usedto produce 52 mg (yield: 34%) oftrans-4-acetylthio-5-(2-hydroxyethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a white powder.

[1514]¹H-NMR (200 MHz, CDCl₃)

[1515] d: 7.40-6.85 (10H, m), 5.11 (1H, d, J=15.1 Hz), 4.00-3.94 (1H,m), 3.86 (1H, d, J=5.4 Hz), 3.80-3.70 (3H, m), 3.60-3.30 (2H, m), 3.08(1H, dd, J=8.0, 18.0 Hz), 2.34 (1H, dd, J=2.0, 18.0 Hz), 2.32 (3H, s)

Example 190trans-5-(2-Hydroxyethyl)aminocarbonyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1516] 25 mg (0.058 mmol) oftrans-4-acetylthio-5-(2-hydroxyethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 189 was subjected to a method similar to that inExample 184 to obtain 5 mg (yield: 22%) oftrans-5-(2-hydroxyethyl)aminocarbonyl-4-mercapto-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1517]¹H-NMR (200 MHz, CDCl₃)

[1518] d: 7.42-6.89 (9H, m), 6.30-6.17 (1H, m), 5.07 (1H, d, J=14.7 Hz),3.91 (1H, d, J=14.7 Hz), 3.78-3.30 (6H, n), 3.08 (1H, dd, J=8.0, 18.0Hz), 2.38 (1H, dd, J=5.2, 18.0 Hz), 2.03 (1H, d, J=7.0 Hz)

Example 191trans-4-Acetylthio-5-(4-pyridylmethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1519] Similarly to Example 186 and starting from 600 mg (1.48 mmol) ofa carboxylic acid product and 4-aminomethylpyridine, 320 mg (yield: 44%)of an amide product was obtained. 300 mg (0.61 mmol) of the amideproduct thus obtained and 346 mg (3.00 mmol) of potassium thioacetatewere then used to produce 98 mg (yield: 34%) oftrans-4-acetylthio-5-(4-pyridylmethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1520]¹H-NMR (200 MHz, CDCl₃)

[1521] d: 8.60-8.57 (2H, m), 7.40-6.90 (12H, n), 5.14 (1H, d, J=15.4Hz), 4.51 (1H, d, J=6.1 Hz), 3.93 (1H, d, J=8.8 Hz), 3.89 (1H, d, J=15.3Hz), 3.76 (1H, s), 3.06 (1H, dd, J=9.1, 18.0 Hz), 2.36 (1H dd, J=1.5,18.0 Hz), 2.34 (3H, s)

Example 192trans-4-Mercapto-5-(4-pyridylmethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1522] 50 mg (0.11 mmol) oftrans-4-acetylthio-5-(4-pyridylmethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneobtained in Example 191 was subjected to a method similar to that inExample 184 to obtain 23 mg (yield: 48%) oftrans-4-mercapto-5-(4-pyridylmethyl)aminocarbonyl-1-(4-phenoxybenzyl)pyrrolidin-2-oneas a colorless oil.

[1523]¹H-NMR. (200 MHz, CDCl₃)

[1524] d: 8.59-8.50 (2H, m), 7.40-6.90 (1H, m), 6.88-6.65 (1H, m), 5.04(1H, d, J=15.0 Hz), 4.46 (2H, d, J=6.2 Hz), 3.87 (1H, d, J=14.6 Hz),3.75 (1H, d, J=4.3 Hz), 3.62-3.45(1H, m), 3.04 (1H, dd, J=8.2, 18.0 Hz),2.36 (1H, dd, J=5.4, 18.0 Hz), 2.05-1.95 (1H, m)

Example 1934-Acetylthio-1-[(1-benzoyl-4-piperidyl)methyl]pyrrolidin-2-one

[1525] 2.28 g (0.02 mol) of 4-aminomethylpiperidine and 2.12 g (0.02mol) of benzaldehyde were dissolved in 20 ml of toluene, and heatedunder reflux for 2 hours with dehydrating. The reaction mixture wasconcentrated, treated with 20 ml of chloroform and 2.23 g (0.022 mol) oftriethylamine, stirred with cooling on ice while being treated dropwisewith 2.81 g (0.022 mol) of benzoyl chloride. After stirring for 2 hours,the reaction mixture was concentrated, treated with 30 ml of acetic acidand 10 ml of water, and stirred at room temperature for 30 minutes. Thereaction mixture was concentrated and partitioned between diethyl etherand water, and the aqueous layer was made basic with an aqueous solutionof sodium hydroxide, and then extracted with chloroform. The chloroformlayer was washed with water and concentrated to obtain 2.71 g (yield:62.1%) of 1-benzoyl-4-aminomethylpiperidine as a colorless oil.

[1526] 1-Benzoyl-4-aminomethylpiperidine thus obtained was subjected toa method similar to that in Example 123 to obtain4-acetylthio-1-[(1-benzoyl-4-piperidyl)methyl]pyrrolidin-2-one.

[1527]¹H-NMR (200 MHz, CDCl₃)

[1528] d: 7.39 (5H, s), 4.81-4.55 (1H, m), 4.13-4.00 (1H, m), 4.00-3.62(1H, m), 3.89 (1H, dd, J=7.3, 12.0 Hz), 3.31 (1H, dd, J=4.5, 12.0 Hz),3.35-3.01 (2H, m), 3.00-2.75 (2H, m), 2.87 (1H, dd, J=8.8, 18.0 Hz),2.38 (1H, dd, J=5.6, 18.0 Hz), 2.35 (3H, s), 2.13-1.80 (1H, m),1.80-1.50 (2H, m), 1.40-1.15 (2H, m).

Example 194trans-4-Acetylthio-3-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1529] 0.70 g (2.0 mmol) of the pyrrolidin-2-one product obtained inExample 15 was dissolved in 15 ml of acetonitrile, treated with 0.5 mlof water, and stirred at 90° C. for 20 minutes. The reaction mixture wasconcentrated, treated with 15 ml of tetrahydrofuran and 0.32 g (2.2mmol) of 1,1-diethoxytrimethylamine, and stirred at 80° C. for 30minutes.

[1530] The reaction mixture was concentrated, and the residue wastreated with 15 ml of 2-propanol, and stirred at room temperature whilebeing treated with 0.15 g (4.0 mmol) of sodium borohydride. Afterstirring for 1 hour, the reaction mixture was concentrated, and theresidue was extracted with ethyl acetate and saturated aqueous sodiumhydrogen carbonate. The ethyl acetate layer was washed with water,concentrated, and subjected to column chromatography on silica geleluting with methanol:chloroform (3:97) to obtain 0.41 g (yield: 68.1%)of an alcohol product as a colorless oil.

[1531] 0.36 g (1.2 mmol) of the alcohol product thus obtained wasdissolved in 10 ml of pyridine, treated with 0.28 g (2.4 mmol) ofmethanesulfonyl chloride, and stirred at 50° C. for 2 hours. Thereaction mixture was concentrated, and the residue was made acidic with2N hydrochloric acid, and then extracted with ethyl acetate. The ethylacetate layer was concentrated and subjected to column chromatography onsilica gel eluting with ethyl acetate: n-hexane (60:40) to obtain 0.12 g(yield: 26.2%) of a cis-mesylate product as a colorless oil.

[1532] 38 mg (0.1 mmol) of the cis-mesylate product thus obtained wasdissolved in 2 ml of N,N-dimethylformamide, treated with 57 mg (0.5mmol) of potassium thioacetate and stirred at 45° C. overnight. Thereaction mixture was extracted with ethyl acetate and water, and theethyl acetate layer was washed with water and concentrated, and theresidue was

[1533] subjected to column chromatography on silica gel eluting withethyl acetate: n-hexane (30:70) to obtain 24 mg (yield: 68%) oftrans-4-acetylthio-3-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one as acolorless oil.

[1534]¹H—NMR (200 MHz, CDCl₃)

[1535] d: 7.40-6.90 (9H, m), 4.49 (1H, d, J=14.7 Hz), 4.37 (1H, d,J=14.7 Hz), 4.30-4.20 (1H, m), 3.66 (1H, dd, J=10.7, 6.6 Hz), 3.12 (1H,dd, J=10.7, 4.3 Hz), 2.92-2.78 (1H, m), 2.33 (3H, s), 1.20 (3H, d, J=7.3Hz)

Example 195trans-4-Mercapto-3-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one

[1536] Starting from 20 mg (0.056 mmol) oftrans-4-acetylthio-3-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one obtainedin Example 194 and similarly to Example 17, 17 mg (yield: 97%) oftrans-4-mercapto-3-methyl-1-(4-phenoxybenzyl)pyrrolidin-2-one wasobtained as a colorless oil.

[1537]¹H-NMR (200 MHz, CDCl₃)

[1538] d: 7.40-6.90 (9H, m), 4.52 (1H, d, J=14.6 Hz), 4.37 (1H, d,J=14.7 Hz), 3.71-3.56 (2H, m), 3.19-3.05 (1H, m), 2.80-2.67 (1H, m),1.44 (1H, d, J=7.9 Hz), 1.26 (3H, d, J=7.3 Hz)

Example 196 S-[5-Oxo-1-(4-phenoxybenzoyl)-3-pyrrolidinyl]ethanethioate

[1539] 3.0 g (29.67 mmol) of 4-hydroxy-2-pyrrolidone and 5050 mg (74.18mmol) of imidazole were dissolved in 15 ml of DMF, treated with 5366 mg(35.60 mmol) of tert-butyldimethylchlorosilane, and stirred at roomtemperature for 24 hours. The reaction mixture was treated with ethylacetate, washed 4 times with water and then with saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the mixture was precipitated from n-hexane:ethyl acetate (1:1)to obtain (yield: 89%) 400 mg (1.86 mmol) of 4-{[tert-butyl(dimethyl)silyl]oxy}-2-pyrrolidinone, which was then dissolved in 4 ml of THF andtreated with 89 mg (2.23 mmol) of 60% sodium hydride at 0° C. andstirred at the same temperature for 15 minutes, and immediately afterbeing treated with a solution of 4-phenoxybenzoyl chloride prepared from477 mg (2.23 mmol) of 4-phenoxybenzoic acid, 389 μl (4.46 mmol) ofoxalyl chloride and 5 μl (catalytic amount) of DMF in 4 ml of THF, themixture was allowed to warm to room temperature and then stirred for 2hours. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed with water, a saturated aqueoussolution of sodium hydrogen carbonate and saturated brine, and driedover anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was purified by preparative thin layerchromatography (eluent: n-hexane:ethyl acetate (3:1)) and dissolved inethyl acetate, washed three times with a saturated aqueous solution ofsodium hydrogen carbonate and then with saturated brine, and dried overanhydrous sodium sulfate. The mixture was concentrated under reducedpressure to obtain (yield: 26%) 100 mg (0.244 mmol) of1-(4-phenoxybenzoyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-pyrrolidinone,which was then dissolved in 1 ml of THF, treated with 244 μl (0.24 mmol)of a 1M solution of tetrabutylammonium fluoride in THF at 0° C. andstirred at the same temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure and purified by preparative thinlayer chromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain(yield: 78%) 30 mg (0.10 mmol) of4-hydroxy-1-(4-phenoxybenzoyl)-2-pyrrolidinone which was dissolved in0.5 ml of toluene together with 26.1 mg (0.15 mmol) ofN,N,N′,N′-tetramethylazodicarboxamide and 38 μl (0.15 mmol) oftributylphosphine, treated with 7.2 μl (0.10 mmol) of thiolacetic acidat 0° C., and then allowed immediately to warm to room temperature, andstirred for 20 hours. 7.2 μl (0.10 mmol) of thiolacetic acid was addedagain and the mixture was stirred for 24 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedtwice with water and then with saturated brine, and dried over anhydroussodium sulfate. After concentrating under reduced pressure, the residuewas purified by preparative thin layer chromatography (eluent:n-hexane:ethyl acetate (1:1)) to obtain 7 mg (yield: 19%) of the titlecompound as a yellow oil.

[1540]¹H-NMR (300 MHz, CDCl₃)

[1541] δ: 7.65-6.95 (9H, m), 4.33 (1H, dd, J=11.9, 6.9 Hz), 4.23-4.14(1H, m), 3.86 (1H, dd, J=11.9, 5.0 Hz), 3.09 (1H, dd, J=18.2, 8.2 Hz),2.61 (1H, dd, J=18.1, 5.8 Hz), 2.38 (3H, s)

Example 197S-((3R)-5-Oxo-1-{4-[(phenylsulfonyl)amino]benzyl}pyrrolidinyl)ethanethioate

[1542] To a mixture of 4.8 g (25.44 mmol) of 4-nitrobenzylaminehydrochloride, 4.4 g (27.98 mmol) of (S)-(−)—O-acetylmalic anhydride and40 ml of acetonitrile was treated dropwise with a solution of 3547 μl(25.44 mmol) of triethylamine in 20 ml of THF at 0° C. Immediately aftercompletion of the dropwise addition, the mixture was allowed to warm toroom temperature, and stirred for 1.5 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in 50 ml of acetylchloride, and stirred at 60° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure, dissolved in ethyl acetate, washedwith water, a saturated aqueous solution of sodium hydrogen carbonateand saturated brine, and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was purified by columnchromatography on silica gel, and the fraction eluted withn-hexane:ethyl acetate (3:1 to 2:3) was concentrated to obtain (yield:51%) 2.0 g (6.84 mmol) of(3S)-1-(4-nitrobenzyl)-2,5-dioxopyrrolidinylacetate, which was dissolvedin a solvent mixture of 11.5 ml of ethanol and 23 ml of THF, treatedwith 259 mg (6.84 mmol) of sodium borohydride at −10° C., and stirred at−13 to −10° C. for 1 hour. 259 mg (6.84 mmol) of sodium borohydride wasadded again, and the mixture was further stirred at −713 to −10° C. for2.5 hours, and treated with a saturated aqueous solution of sodiumhydrogen carbonate, ethyl acetate and saturated brine to effect apartition, and the aqueous layer was extracted twice with ethyl acetateand the organic layers were combined and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wasdissolved in 15 ml of trifluoroacetic acid, treated with 1093 μl (6.84mmol) of triethylsilane and stirred at room temperature for 10 minutes.The reaction mixture was concentrated under reduced pressure, dissolvedin ethyl acetate, washed twice with a saturated aqueous solution ofsodium hydrogen carbonate, twice with a saturated aqueous solution ofsodium hydrogen carbonate, and then with 0.1 N hydrochloric acid andsaturated brine, and dried over anhydrous sodium sulfate. The mixturewas concentrated under reduced pressure, dissolved in 10 ml ofchloroform, treated with 1292 μl (13.67 mmol) of acetic anhydride and1107 μl (13.67 mmol) of pyridine and stirred at room temperature for 5hours. The reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with 1N hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate.After concentrating under reduced pressure, the residue was purified bycolumn chromatography on silica gel, and the fraction eluted withn-hexane:ethyl acetate (33:67) was concentrated to obtain (3 steps,yield: 48%) 200 mg (0.72 mmol) of(3S)-1-(4-nitrobenzyl)-5-oxopyrrolidinyl acetate, which was stirredvigorously in the presence of 258 mg of 10% Pd/C in a solvent mixture of1 ml of formic acid and 2 ml of a 1N solution of hydrochloric acid inethyl acetate under hydrogen atmosphere for 1 hour, and the reactionmixture was filtered through Celite, concentrated under reducedpressure, dissolved in ethyl acetate, washed with a saturated aqueoussolution of sodium hydrogen carbonate and saturated brine, and driedover anhydrous sodium sulfate. 0.5 ml of a 4N solution of hydrochloricacid in ethyl acetate was added, and the mixture was concentrated underreduced pressure to obtain (yield: 82%) 167 mg (0.59 mmol) of(3S)-1-(4-aminobenzyl)-5-oxopyrrolidinyl acetate hydrochloride, whichwas then dissolved in 2 ml of chloroform together with 82 μl (0.64 mmol)of benzenensulfonyl chloride, and treated dropwise with 172 μl (1.23mmol) of triethylamine at 0° C. After completion of the dropwiseaddition, the mixture was stirred at 0° C. for 30 minutes. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate, washed with 0.1 N hydrochloric acid and saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was purified by preparative thin layerchromatography (eluent: n-hexane:ethyl acetate (1:2)) to obtain (yield:71%) 130 mg (0.37 mmol) of(3S)-5-oxo-1-{4-[(phenylsulfonyl)amino]benzyl}pyrrolidinyl acetate,which was then dissolved in a solution prepared previously by adding 519μl (7.3 mmol) of acetyl chloride dropwise to 1 ml of ethanol, andstirred at 50° C. for 1.5 hours. The reaction mixture was concentratedunder reduced pressure to obtain (yield: 92%) 116 mg (0.335 mmol) ofN-(4-{[(4S)-4-hydroxy-2-oxypyrrolidinyl]methyl}phenyl)benzenesulfonamide,which was dissolved in 1 ml of acetonitrile together with 44 μl (0.57mmol) of methanesulfonyl chloride, and treated dropwise with a solutionof 79.4 μl (1.07 mmol) of triethylamine in 1 ml of acetonitrile at 0° C.After completion of the dropwise addition, the mixture was stirred at 0°C. for 10 minutes, and treated dropwise again with 44 μl (0.57 mmol) ofmethanesulfonyl chloride and a solution of 79.4 μl (1.07 mmol) oftriethylamine in 0.5 ml of acetonitrile. After completion of thedropwise addition followed by stirring at 0° C. further for 10 minutes,the reaction mixture was concentrated under reduced pressure, dissolvedin ethyl acetate, washed with water and saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was purified by preparative thin layer chromatography(eluent: chloroform:methanol (10:1)) to obtain (yield: 9%) 13 mg (0.03mmol) of (3S)-5-oxo-1-{4-[(phenylsulfonyl)amino]benzyl}pyrrolidinylmethanesulfonate, which was dissolved in 1 ml of DMF, treated with 8 mg(0.02 mmol) of cesium carbonate and a solution of 11 μl (0.15 mmol) ofthiolacetic acid in 1 ml of DMF, and stirred under nitrogen atmosphereat room temperature for 24 hours. 10 mg (0.03 mmol) of cesium carbonateand a solution of 4 μl (0.06 mmol) of thiolacetic acid in 1 ml of DMFwere added again, and the mixture was stirred under nitrogen atmosphereat room temperature for 11 days. The reaction mixture was treated withethyl acetate, washed three times with water and then with saturatedbrine, and dried over anhydrous sodium sulfate. After concentratingunder reduced pressure, the residue was purified by preparative thinlayer chromatography (eluent:n-hexane:ethyl acetate (1:2)) to obtain 1.6mg (yield: 13%) of the title compound as a colorless oil.

[1543]¹H-NMR (300 MHz, CDCl₃)

[1544] δ: 7.88-7.01 (9H, m), 6.74 (1H, m), 4.51-4.06 (2H, m), 4.08-3.99(1H, m), 3.82-3.67 (1H, n), 3.23-3.08 (1H, m), 2.90 (1H, dd, J=17.4, 8.9Hz), 2.52-2.35 (1H, m), 2.31 (3H, s)

Example 198S-{(3R)-1-{4-(1,3-benzodioxol-5-yloxy)benzyl]-5-oxopyrrolidinyl}ethanethioate

[1545] 3.0 g (24.17 mmol) of 4-fluorobenzaldehyde, 3.3 g (24.17 mmol) of3,4-methylenedioxyphenol and 3.3 g (24.17 mmol) of potassium carbonatewere stirred in 20 ml of DMF at 120° C. for 22 hours, and the reactionmixture was treated with ethyl acetate and washed 4 times with water andthen with saturated brine and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was purified by columnchromatography on silica gel, and the fraction eluted withn-hexane:ethyl acetate (92:8) was concentrated to obtain (yield: 25%)2.9 g (11.95 mmol) of 4-(1,3-benzodioxol-5-yloxy)benzaldehyde, which wasstirred together with 1030 mg (14.82 mmol) of hydroxylaminehydrochloride and 1486 mg (17.57 mmol) of sodium hydrogen carbonate in asolvent mixture of 41 ml of ethanol and 6 ml of water at 60° C. for 1hour, and the reaction mixture was concentrated under reduced pressure,dissolved in ethyl acetate, washed twice with water and with saturatedbrine, and dried over anhydrous sodium sulfate. After concentratingunder reduced pressure, the residue was stirred vigorously together with684 μl (11.95 mmol) of acetic acid in the presence of 258 mg of 10% Pd/Cin 55 ml of methanol under hydrogen atmosphere for 2 hours, and thereaction mixture was filtered through Celite, concentrated under reducedpressure, treated with ethyl acetate, treated dropwise with 3 ml of a 4Nsolution of hydrochloric acid in ethyl acetate, concentrated underreduced pressure, precipitated from ethyl acetate to obtain (2 steps,yield: 77%) 2.0 g (7.15 mmol) of 4-(1,3-benzodioxol-5-yloxy)benzylaminehydrochloride, which was treated with 1244 mg (7.87 mmol) of(S)-(−)—O-acetylmalic anhydride and 10 ml of acetonitrile and thentreated dropwise with a solution of 996 μl (7.15 mmol) of triethylaminein 5 ml of THF at 0° C. After completion of the dropwise addition, themixture was allowed immediately to warm to room temperature, and stirredfor 2 hours. The reaction mixture was concentrated under reducedpressure, dissolved in 20 ml of acetyl chloride, and stirred at 60° C.for 30 minutes. The reaction mixture was concentrated under reducedpressure, dissolved in ethyl acetate, washed with water, a saturatedaqueous solution of sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. After concentrating under reducedpressure, the residue was purified by column chromatography on silicagel, and the fraction eluted with n-hexane:ethyl acetate (3:1) wasconcentrated to obtain (yield: 92%) 1592 mg (4.15 mmol) of(3S)-1-{4-(1,3-benzodioxol-5-yloxy)benzyl]-2,5-dioxopyrrolidinylacetate, which was dissolved in a solvent mixture of 7 ml of ethanol and14 ml of THF, treated with 314 mg (8.30 mmol) of sodium borohydride at−14° C., and stirred at −14 to −10° C. for 3 hours. The reaction mixturewas treated with a saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate and saturated brine to effect a partition, andthe aqueous layer was extracted twice with ethyl acetate and the organiclayers were combined and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was dissolved in 9 mlof trifluoroacetic acid, treated with 663 μl (4.15 mmol) oftriethylsilane and stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, dissolved inethyl acetate, washed with a saturated aqueous solution of sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wasdissolved in a solution prepared by adding 639 μl (83 mmol) of acetylchloride dropwise to 15 ml of ethanol, and stirred at 50° C. for 1.5hours. The reaction mixture was concentrated under reduced pressure, andpurified by column chromatography on silica gel, and the fraction elutedwith n-hexane: acetone (55:45) was concentrated to obtain (3 steps,yield: 34%) 250 mg (0.76 mmol) of(4S)-1-[4-(1,3-benzodioxol-5-yloxy)benzyl]-4-hydroxy-2-pyrrolidinone,which was dissolved in 2 ml of chloroform together with 82 μl (1.07mmol) of methanesulfonyl chloride, and treated dropwise with a solutionof 149 μl (1.07 mmol) of triethylamine in 1 ml of chloroform at 0° C.over a period of 10 minutes. After completion of the dropwise addition,the mixture was stirred at 0° C. for 10 minutes. The reaction mixturewas concentrated under reduced pressure, dissolved in ethyl acetate,washed with water and saturated brine, and dried over anhydrous sodiumsulfate. The mixture was concentrated under reduced pressure to obtain(quantitative) 200 mg (0.53 mmol) of(3S)-1-[4-(1,3-benzodioxol-5-yloxy)benzyl]-5-oxopyrrolidinylmethanesulfonate, which was dissolved in 1 ml of DMF, treated with 22 mg(0.37 mmol) of cesium carbonate and a solution of 191 μl (2.67 mmol) ofthiolacetic acid in 1 ml of DMF, and stirred under nitrogen atmosphereat room temperature for 48 hours. The reaction mixture was treated withethyl acetate, washed 5 times with water and then with saturated brine,and dried over anhydrous sodium sulfate. After concentrating underreduce pressure, the residue was purified by preparative thin layerchromatography (eluent: n-hexane:ethyl acetate (1:1)) to obtain 88 mg(yield: 43%) of the title compound as a brown oil.

[1546]¹H-NMR (300 MHz, CDCl₃)

[1547] δ: 7.17-6.47 (7H, m), 5.97 (2H, s), 4.44 (1H, d, J=14.6 Hz), 4.38(1H, d, J=14.7 Hz), 4.09-4.00 (1H, m), 3.74 (1H, dd, J=10.6, 7.5 Hz),3.15 (1H, dd, J=10.6, 4.9 Hz), 2.91 (1H, dd, J=17.4, 9.0 Hz), 2.41 (1H,dd, J=17.4, 6.0 Hz), 2.31 (3H, s)

Example 199(R)-4-Acetylthio-1-[4-(4′-bromophenoxy)benzyl)pyrrolidin-2-one

[1548] Using a method similar to that in Example 125 and starting from4-(4′-bromophenoxy)benzylamine prepared from 4-fluorobenzaldehyde and4-bromophenol and (S)-O-acetylmalic anhydride,(R)-4-acetylthio-1-[4-(4′-bromophenoxy)benzyl]pyrrolidin-2-one wasobtained as a pale orange powder.

[1549]¹H-NMR (200 MHz, CDCl₃)

[1550] δ: 7.44 (2H, d, J=9.0 Hz), 7.20 (2H, d, J=8.7 Hz), 6.96 (2H, d,J=8.7 Hz), 6.89 (2H, d, J=9.0 Hz), 4.43 (2H, s), 4.14-3.98 (1H, m), 3.76(1H, dd, J=10.6, 7.5 Hz), 3.17 (1H, dd, J=10.6, 5.0 Hz), 2.92 (1H, dd,J=17.4, 8.9 Hz), 2.43 (1H, dd, J=17.4, 6.0 Hz), 2.32 (3H, s)

Example 200 (R)-4-Mercapto-1-[4-(4′-bromophenoxy)benzyl]pyrrolidin-2-one

[1551] Using a method similar to that in Example 126 and starting from200 mg (0.48 mmol) of(R)-4-acetylthio-1-[4-(4′-bromophenoxy)benzyl]pyrrolidin-2-one obtainedin Example 199, 180 mg (yield: 77%) of(R)-4-mercapto-1-[4-(4′-bromophenoxy)benzyl]pyrrolidin-2-one wasobtained as a pale pinkish oil.

[1552]¹H-NMR (200 MHz, CDCl₃)

[1553] δ: 7.44 (2H, d, J=9.0 Hz), 7.23 (2H, d, J=8.7 Hz), 6.96 (6H, d,J=8.7 Hz), 6.88 (2H, d, J=9.0 Hz), 4.49 (1H, d, J=14.9 Hz), 4.37 (1H, d,J=14.9 Hz), 3.66 (1H, dd, J=9.8, 7.2 Hz), 3.55-3.46(1H, m), 3.17(1H, dd,J=9.8, 4.8 Hz), 2.93 (1H, dd, J=17.2, 8.0 Hz), 2.43 (1H, dd, J=17.2, 6.1Hz), 1.87 (1H, d, J=6.7 Hz)

Example 201 4-Acetylthio-1-(2-dibenzofuranmethyl)pyrrolidin-2-one

[1554] (1) 10.0 g (60 mmol) of dibenzofuran was dissolved in 300 ml ofchloroform, and stirred with cooling on ice. 9.8 ml (89 mmol) oftitanium tetrachloride was added dropwise over a period of 30 minutes,and the mixture was stirred further for 1.5 hours with cooling on ice.To this solution, 8.1 ml (89 mmol) of dichloromethyl methyl ether wasadded dropwise over a period of 30 minutes, and the mixture was stirredfurther for 2.5 hours with cooling on ice. Ice was added slowly to thereaction mixture, which was then allowed to warm to room temperaturewith stirring for 1 hour. After concentrating under reduced pressurefollowed by extracting twice with ethyl acetate, the organic layerobtained was washed with water and saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel elutingwith hexane:ethyl acetate (95:5) to obtain 3.50 g (yield: 30%) of2-dibenzofuran carboxyaldehyde as an orange powder.

[1555]¹H-NMR (300 MHz, CDCl₃)

[1556] δ: 10.14 (1H, s), 8.51 (1H, d, J=1.4 Hz), 8.03 (1H, d, J=8.5 Hz),8.03 (1H, dd, J=8.2, 1.0 Hz), 7.70 (1H, d, J=8.5 Hz), 7.63 (1H, d, J=8.2Hz), 7.54 (1H, ddd, J=7.2, 7.2, 1.4 Hz), 7.42 (1H, ddd, J=7.4, 7.4, 1.0Hz)

[1557] (2) Then using a method similar to that in Example 30 andstarting from 1.22 g (5.6 mmol) of 2-chloromethyldibenzofuran and 1.16 g(6.7 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 537 mg (yield: 29%)of 4-acetylthio-1-(2-dibenzofuranmethyl)pyrrolidin-2-one was obtained asa brown oil.

[1558]¹H-NW (300 MHz, CDCl₃)

[1559] δ: 7.95 (1H d, J=7.4 Hz), 7.84 (1H, d, J=1.4 Hz), 7.57 (1H, d,J=8.2 Hz), 7.53 (1H, d, J=8.4 Hz), 7.47 (1H, ddd, J=7.4, 7.4, 1.4 Hz),7.35 (2H, m), 4.67 (1H, d, J=14.6 Hz), 4.56 (1H, d, J=14.6 Hz), 4.06(1H, m), 3.78 (1H, dd, J=10.7, 7.5 Hz), 3.19 (1H, dd, J=10.7, 4.8 Hz),2.95 (1H, dd, J=17.5, 9.0 Hz), 2.46 (1H, dd, J=17.5, 5.9 Hz), 2.28 (3H,s)

Example 202 4-Mercapto-1-(2-dibenzofuranmethyl)pyrrolidin-2-one

[1560] Using a method similar to that in Example 31 and starting from282 mg (0.80 mmol) of4-acetylthio-1-(2-dibenzofuranmethyl)pyrrolidin-2-one obtained inExample 201, 207 mg (yield: 87%) of4-mercapto-1-(2-dibenzofuranmethyl)pyrrolidin-2-one was obtained as acolorless oil.

[1561]¹H-NMR (300 MHz, CDCl₃)

[1562] δ: 7.95 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=1.4 Hz), 7.57 (1H, d,J=8.2 Hz), 7.53 (1H, d, J=8.5 Hz), 7.47 (1H, ddd, J=7.4, 7.3, 1.4 Hz),7.35 (2H, m), 4.66 (1H, d, J=14.6 Hz), 4.59 (1H, d, J=14.6 Hz), 3.68(1H, dd, J=10.2, 7.2 Hz), 3.54 (1H, m), 3.19 (1H, dd, J=10.2, 5.1 Hz),2.95 (1H, dd, J=17.1, 8.2 Hz), 2.45 (1H, dd, J=17.1, 6.1 Hz), 1.85 (1H,d, J=6.8 Hz)

Example 2034-Acetylthio-1-[4-(N-phenyl-N-p-toluenesulfonyl)aminobenzyl]pyrrolidin-2-one

[1563] (1) 20.0 g (148 mmol) of acetoanilide and 13.9 g (76.5 mmol) of4-bromobenzonitrile were dissolved under nitrogen atmosphere at 120° C.and treated with 23.0 g (161 mmol) of copper (I) oxide and 18.0 g (130mmol) of potassium carbonate and then stirred under nitrogen atmosphereat 200° C. for 18 hours. The reaction mixture was treated with ethylacetate and filtered, and the ethyl acetate layer was washed with waterand saturated brine and dried over anhydrous sodium sulfate. Afterconcentrating under reduced pressure, the residue was subjected tocolumn chromatography on silica gel, and the fraction eluted withhexane:ethyl acetate (80:20) was concentrated under reduced pressure andcrystallized from hexane-ethyl acetate to obtain 5.51 g (yield: 37%) of4-cyano-N-phenylaniline as a pale yellow needle.

[1564]¹H-NM (300 MHz, CDCl₃)

[1565] δ: 7.48 (2H, d, J=8.7 Hz), 7.36 (2H, m), 7.17 (2H, m), 7.12 (1H,m), 6.97 (2H, d, J=8.7 Hz), 6.07 (1H, s)

[1566] (2) 1.00 g (5.15 mmol) of 4-cyano-N-phenylaniline was dissolvedin 40 ml of toluene, treated with 618 mg (15.5 mmol) of 60% sodiumhydride and 2.95 g (15.5 mmol) of p-toluenesulfonyl chloride, and heatedat 100° C. for 3 days with stirring. The reaction mixture was treatedwith water and extracted twice with ethyl acetate, and the ethyl acetatelayer was washed with water and saturated brine, and dried overanhydrous sodium sulfate. After concentrating under reduced pressure,the residue was subjected to column chromatography on silica gel elutingwith hexane:ethyl acetate (80:20) to recover 510 mg of the startingmaterial 4-cyano-N-phenylaniline and then obtain as an intendedsubstance 4-cyano-N-phenyl-N-p-toluenesulfonylaniline. The recoveredstarting material was subjected to the same reaction and combined with4-cyano-N-phenyl-N-p-toluenesulfonylaniline to give 1.47 g (yield: 82%)in total as a pale yellow powder.

[1567]¹H-NMR (300 MHz, CDCl₃)

[1568] δ: 7.61 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.7 Hz), 7.38 (3H, m),7.34 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.3 Hz), 7.21 (2 μl m), 2.44 (3H,s)

[1569] (3) 1.26 g (3.62 mmol) of4-cyano-N-phenyl-N-p-toluenesulfonylaniline was dissolved in a mixtureof 36.2 ml of toluene and 7.24 ml of dichloromethane under argonatmosphere and cooled to −78° C. and treated with 5.43 ml (5.43 mmol) ofa 1M solution of diisobutylaluminium hydride in toluene. After stirringat −78° C. for 0.5 hour, the mixture was stirred further for 2 hours atroom temperature. The reaction mixture was treated with 7.24 ml ofmethanol and 7.24 ml of 2N aqueous hydrochloric acid and extracted twicewith ethyl acetate, and the ethyl acetate layer was washed twice withwater and once with saturated brine, and dried over anhydrous sodiumsulfate. After concentrating under reduced pressure, the residue wassubjected to column chromatography on silica gel, and the fractioneluted with hexane:ethyl acetate (80:20-70:30) was concentrated underreduced pressure to obtain 1.04 g (yield: 82%) of4-formyl-N-phenyl-N-p-toluenesulfonylaniline as a pale yellow powder.

[1570]¹H-NMR (300 MHz, CDCl₃)

[1571] δ: 9.94 (1H, s), 7.79 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz),7.40 (2H, d, J=8.3 Hz), 7.36 (3H, m), 7.29 (2H, d, J=8.3 Hz), 7.25 (2H,m), 2.44 (3H, s)

[1572] (4) 1.00 g (2.85 mmol) of4-formyl-N-phenyl-N-p-toluenesulfonylaniline was dissolved in 200 ml ofmethanol, treated with 108 mg (2.85 mmol) of sodium borohydride andstirred at room temperature for 0.5 hours. The reaction mixture wasconcentrated under reduced pressure, treated with ethyl acetate, washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The mixture was concentrated under reduced pressure to obtain 1.05 g(quantitative yield) of4-hydroxymethyl-N-phenyl-N-p-toluenesulfonylaniline as a colorless oil.

[1573]¹H-NMR (300 MHz, CDCl₃)

[1574] δ: 7.58 (2H, d, J=8.3 Hz), 7.20-7.35 (1H, m), 4.67 (2H, d, J=5.8Hz), 2.43 (3H, s), 1.69 (1H, t, J=5.8 Hz)

[1575] (5) 1.05 g (2.85 mmol) of4-hydroxymethyl-N-phenyl-N-p-toluenesulfonylaniline, 231 μl (2.85 mmol)of pyridine and 229 μl (3.14 mmol) of thionyl chloride were processedsimilarly to Example 159 to obtain 1.05 g (quantitative yield) of4-chloromethyl-N-phenyl-N-p-toluenesulfonylaniline as a colorless oil.

[1576]¹H-NMR (300 MHz, CDCl₃)

[1577] δ: 7.59 (2H, d, J=8.3 Hz), 7.21-7.36 (1H, m), 4.54 (2H, s), 2.44(3H, s)

[1578] (6) Similarly to Example 30 and starting from 1.05 g (2.82 mmol)of 4-chloromethyl-N-phenyl-N-p-toluenesulfonylaniline, 494 mg (2.85mmol) of 4-trimethylsilyloxypyrrolidin-2-one and 160 mg (2.85 mmol) ofpowdered potassium hydroxide, 439 mg (yield: 35%) of4-hydroxy-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-oneas a tan oil.

[1579]¹H-NMR (300 MHz, CDCl₃)

[1580] δ: 7.57 (2H, d, J=8.3 Hz), 7.15-7.35 (1H, m), 4.50 (1H, m), 4.48(1H, d, J=15.1 Hz), 4.40 (1H, d, J=15.1 Hz), 3.51 (1H, dd, J=10.9, 5.5Hz), 3.19 (1H, dd, J=10.9, 1.9 Hz), 2.73 (1H, dd, J=17.3, 6.4 Hz), 2.44(3H, s), 2.42 (1H, dd, J=17.3, 2.3 Hz)

[1581] (7) Starting from 390 mg (0.893 mmol) of4-hydroxy-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-one,374 μl (2.68 mmol) of triethylamine and 208 μl (2.68 mmol) ofmethanesulfonyl chloride, 419 mg (yield: 91%) of4-methanesulfonyloxy-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-onewas obtained as a colorless oil.

[1582]¹H-NMR (300 MHz, CDCl₃)

[1583] δ: 7.57 (2H, d, J=8.3 Hz), 7.15-7.35 (11H, m), 5.28 (1H, m), 4.48(1H, d, J=15.6 Hz), 4.42 (1H, d, J=15.6 Hz), 3.65 (1H, dd, J=12.1, 5.5Hz), 3.50 (1H, dd, J=12.1, 1.9 Hz), 2.98 (3H, s), 2.86 (1H, dd, J=17.9,6.8 Hz), 2.70 (1H, dd, J=17.9, 2.3 Hz), 2.44 (3H, s)

[1584] (8) Starting from 350 mg (0.680 mmol) of4-methanesulfonyloxy-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-oneand 155 mg (1.36 mmol) of potassium thioacetate, 268 mg (yield: 80%) of4-acetylthio-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-onewas obtained as a colorless oil.

[1585]¹H-NMR (300 MHz, CDCl₃)

[1586] δ: 7.57 (2H, d, J=8.3 Hz), 7.20-7.36 (9H, m), 7.16 (2H, d, J=8.3Hz), 4.45 (1H, d, J=15.1 Hz), 4.39 (1H, d, J=15.1 Hz), 4.05 (1H, n),3.74 (1H, dd, J=10.6, 7.7 Hz), 3.16 (1H, dd, J=10.6, 4.9 Hz), 2.90 (1H,dd, J=17.5, 8.9 Hz), 2.44 (3H, s), 2.40 (1H, m), 2.31 (3H, s)

Example 2044-Mercapto-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-one

[1587] Starting from 120 mg (0.234 mmol) of4-acetylthio-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-oneobtained in Example 203 and 345 μl (4.85 mmol) of acetyl chloride and bya method similar to that in Example 126, 65.3 mg (yield: 59%) of4-mecapto-1-[4-(N-phenyl-N-p-toluenesulfonylamino)benzyl]pyrrolidin-2-onewas obtained as a white powder.

[1588]¹H-NMR (300 MHz, CDCl₃)

[1589] δ: 7.57 (2H, d, J=8.3 Hz), 7.15-7.36 (1H, m), 4.45 (1H, d, J=5.5Hz), 4.40 (1H, d, J=15.5 Hz), 3.64 (1H, dd, J=10.2, 7.4 Hz), 3.54 (1H,m), 3.16 (1H, dd, J=10.2, 4.9 Hz), 2.90 (1H, dd, J=17.3, 8.1 Hz), 2.44(3H, s), 2.40 (1H, dd, J=17.3, 6.0 Hz), 1.86 (1H, d, J=6.4 Hz)

[1590] Experiment 1 Production of Recombinant Human MMP-13 Enzyme

[1591] Based on the sequence described in the literature by Freije, J.M. et al (Journal of Biological Chemistry, 269: 16766-16773, 1994) andusing a PCR method known per se, a human MMP-13 cDNA was obtained.

[1592] A pBlueBac4 (Invitrogen) and a Baculovirus vector Bac-N-Blue(Invitrogen) to each of which the human MMP-13 cDNA obtained above wasintegrated were co-transfected to an Sf9 cell to obtain aMMP-13-expressing recombinant virus.

[1593] The recombinant virus thus obtained was infected to a High-Fivecell (Invitrogen), and the culture supernatant after three days wasemployed as an enzyme solution. Experiment 2 Assay of MMP-13 inhibitingactivity

[1594] 75 μl of a sample containing the recombinant human MMP-13, 200 mMsodium chloride, 20 mM calcium chloride, 0.1% Brij 35, 1 mM2-metcaptoethanol, 200 mM tris-HCl buffer solution (pH7.5) and a testsubstance at various concentration was treated with 25 μL of 40MMOCAc-Pro-Leu-Gly-Leu-A₂pr(DNP)-Ala-Arg-NH₂ (PEPTIDE KENKYUSHO) toinitiate a reaction and kept at 37° C. for 2 hours, and then 100 μl of500 mM sodium acetate-HCl buffer solution (pH3.0) was added to terminatethe reaction.

[1595] The level of liberated MOCAc-Pro-Leu-Gly was determined using afluorophotometer (MTP-32/F2: CORONA DENKI) at the excitation wavelengthof 330 nm and the fluorescent wavelength of 405 nm. The fluorescentlevel of the reaction in the absence of a test substance was regarded as100%, and the concentration of each test substance required forachieving 50% inhibition was indicated as IC₅₀.

[1596] The followings are the structures of the compositions of Examplestogether with their IC₅₀s. TABLE 1

Example m R1 IC₅₀ (μM) 1 0 H 0.005 2 0 C₂H₅ >10 3 0 C₂H₄CO₂Et >10 4 0CH₂Ph >10 5 0 COCH₃ 0.03 6 0 COPh 0.002 10 1 COCH₃ 0.4 11 0

0.1

[1597] TABLE 2

Example R1 Y IC₅₀ (μM) 7 COCH₃ CH₃ 0.05 8 H CH₃ 0.02 9 C₂H₄CO₂Et OH 1

[1598] TABLE 3

Example R1 * IC₅₀ (μM) 15 COCH₃ 0.01 16 COPh 0.002 17 H 0.005 18CH₂OCOBu^(t) 0.03 21 COCH₃ (S) 4 22 H (S) 0.3 24 COCH₃ (R) 0.009 25 H(R) 0.003 49 H₂NCO— 0.00065 50 MeNHCO— 0.003 51 EtNHCO— 0.001 52n-PrNHCO— 0.002 53 PhNHCO— 0.001 54 PhCH₂NHCO— 0.0015 55 MeCONHCO—0.0013 56 PhCONHCO— 0.0014 57 EtOOCNHCO— 0.00081 58 EtOOCCH₂NHCO— 0.000759 HOOCCH₂NHCO— 0.002 60 EtOOCCH₂CH₂NHCO— 0.0009 61 HOOCCH₂CH₂NHCO—0.0018 62 (CH₃)₂NCO— 3 63

2 64 EtCO— 0.0032 65 n-PrCO— 0.0013 66 n-BuCO— 0.001 67 iso-PrCO— 0.01168 PhCH₂CO— 0.002 69 4-Cl—PhCH₂CO— 0.02 70 Ph₂CHCO— 0.002 71 EtOOCCH₂CO—0.00089 72 tert-BuOOCCH₂CO— 0.0024 73 HOOCCH₂CO— 0.011 74 EtOOCCH₂CH₂CO—0.0054 75 HOOCCH₂CH₂CO— 0.008 76 MeNHCS— 0.0012 77 EtNHCS— 0.0016 78MeOOCS— >10 79 EtS— 0.1 80 n-C₆H₁₃S— 1.0 81 tert-BuS— 1 82 EtOOCCH₂S—0.05 83 HOOCCH₂S— 0.4 84 EtOOCCH₂CH₂S— 0.032 85 HOOCCH₂CH₂S— 0.46 862-(HOOC)—PhS— 0.5 87 2-(O₂N)—PhS— 0.6 88

0.67 89 Me— 0.7 90 HOCH₂CH₂— 5 91 HOOCCH₂— 1 92 EtOOCCH₂CH₂— 2 93HOOCCH₂CH₂— 6 94 4-Br—PhCH₂— 0.3 95 4-(MeOOC)—PhCH₂— 0.4 964-(HOOC)—PhCH₂— 0.7 97 PhSO₂CH₂CH₂— 2 98 MeOCH₂— 0.2 99

0.007 100 MeCONHCH₂— 2 101 tert-BuCONHCH₂— 3 102 PhCONHCH₂— 0.1 103EtOOCNHCH₂— 0.3 104

0.2 105

0.04 106

0.02 107 EtOOC— 0.03

[1599] TABLE 4

Example R1 IC₅₀ (μM) 40 COCH₃ 1 41 H 0.2

[1600] TABLE 5

relative Ex- configura- ample tion R1 Y IC₅₀ (μM) 20 COCH₃ CH₂OH 0.01 38COCH₃ CH₂OCH₂Ph 0.005 39 H CH₂OCH₂Ph 0.009 175 cis Ac Me 0.1 175 cis HMe 0.05 177 trans Ac Me 0.002 178 trans H Me 0.005 179 trans Ac iso-Bu0.009 180 trans H iso-Bu 0.02 181 trans Ac PhCH₂ 0.008 182 trans H PhCH₂0.02 183 trans H PhCH₂ 0.02 184 trans H n-PrNHCOOCH₂ 0.0023 185 trans Ac

0.006 186 trans Ac EtOOCCH₂NHCO 0.05 187 trans Ac H₂NCO 0.36 188 trans HH₂NCO 0.013 189 trans Ac HOCH₂CH₂NHCO 0.089 190 trans H HOCH₂CH₂NHCO0.025 191 trans Ac

0.12 192 trans H

0.019

[1601] TABLE 6

relative Example configuration R1 Y IC₅₀ (μM) 194 trans Ac Me— 0.03 195trans H Me— 0.006

[1602] TABLE 7

Example m O * Y IC₅₀ (μM) 12 0 S—S ═O 0.009 13 1 S—S ═O >10 14 0 S ═O0.1 19 0 S—S H 0.2 23 0 S—S (S, S) H >10 26 0 S—S (R, R) H 0.07

[1603] TABLE 8

Example R1 IC₅₀ (μM) 27 COCH₃ >10 28 COPh 1 29 H 2

[1604] TABLE 9

Example R1 R^(c) R^(d) R^(e) R^(f) R^(g) IC₅₀ (μM) 30 Ac H H H H F 0.0131 H H H H H F 0.003 32 Ac H H H H Cl 0.008 33 H H H H H Cl 0.005 34 AcH H H H Br 0.01 35 H H H H H Br 0.006 36 Ac H H H H OCH₃ 0.05 37 H H H HH OCH₃ 0.005 112 Ac H H F H H 0.02 113 H H H F H H 0.004 114 Ac H H H FH 0.01 115 H H H H F H 0.004 116 Ac H H H H F 7 117 Ac H H H H F 0.007118 H H H H H F 0.002 119 Ac H H F H F 0.01 120 H H H F H F 0.007 121 AcH H H F F 0.02 122 H H H H F F 0.02 123 Ac H H H H Me 0.0089 124 Ac H HH H Et 0.0070 125 Ac H H H H Cl 0.0061 126 H H H H H Cl 0.0017 127 Ac HH H H Me 0.01 128 H H H H H Me 0.007 129 Ac H H H H CF₃ 0.03 130 H H H HH CF₃ 0.01 131 Ac H H H H COOEt 0.02 132 H H H H H COOEt 0.0033 133 Ac HH H H COOH >10 134 Ac H H H H CONH₂ 0.029 135 H H H H H CONH₂ 0.0092 136Ac H H H H OH 0.009 137 H H H H H OH 0.003 138 Ac H H H H OEt 0.02 139 HH H H H OEt 0.006 140 Ac H H H H OCF₃ 0.02 141 H H H H H OCF₃ 0.01 142Ac H H H H NO₂ 0.053 143 H H H H H NO₂ 0.011 144 Ac H H H H NHCOMe0.0027 145 H H H H H NHCOMe 0.0013 146 Ac H H H H NHSO₂Me 0.025 147 H HH H H NHSO₂Me 0.0012 148 Ac H H H H NHCONHEt 0.025 149 H H H H HNHCONHEt 0.0035 150 Ac NO₂ H H H H 5.5 151 Ac H NO₂ H H H >10 152 Ac HNHSO₂Me H H H >10 153 H H NHSO₂Me H H H 4 199 Ac H H H H Br 0.006 200 HH H H H Br 0.002

[1605] TABLE 10

Example R1 X¹ X² IC₅₀ (μM) 154 Ac CH₂ S 0.02 155 H CH₂ S 0.007 159 AcCH₂ CH₂ 0.5 160 H CH₂ CH₂ 0.09 161 Ac CH₂ CO 0.2 162 H CH₂ CO 0.02 163Ac CH₂ OCH₂ 0.5 164 H CH₂ OCH₂ 0.08 165 Ac CH₂ CH₂O 1 166 H CH₂ CH₂O 0.1167 Ac CH₂ CH₂CH₂ 0.4 168 H CH₂ CH₂CH₂ 0.07 169 Ac CH₂CH₂ O 7 170 HCH₂CH₂ O 0.5 171 Ac CH₂ SO >10 172 H CH₂ SO >10 173 Ac CH₂ SO₂ >10 174 HCH₂ SO₂ 0.51 196 Ac CO O >10

[1606] TABLE 11

Example R1 T IC₅₀ (μM) 156 Ac

0.7 157 Ac

0.006 158 H

0.004 193 Ac

>10 198 Ac

0.012 201 Ac

0.3 202 H

0.1 203 Ac

>10 204 H

3.9

[1607] TABLE 12

Example R^(h) R^(i) IC₅₀ (μM) 108 H AcS 0.3 109 H HS 0.06 110 AcS H 0.25111 HS H 0.017

[1608] TABLE 13

Example R1 Y R^(g) IC₅₀ (μM) 42 COCH₃ ═O H 0.07 43 COCH₃ ═O Br 0.02 44COPh ═O H 0.01 45 H ═O H 0.04 46 COCH₃ H H >10 47 COPh H H 4 48 H H H 5

Example 3 Assay of Cartilage Collagen Degradation Inhibiting Activity

[1609] A nasal cartilage was isolated aseptically from a sacrificed cow,and preincubated in a Dulbecco's modified eagle medium containing 5%heat-inactivated fetal bovine serum, 100 units/ml of penicillin G and100 units/ml of streptomycin at 37° C. under 5% CO₂ and 95% air for 3days. After completing the preincubation, a cartilage piece weighingabout 10 mg was prepared and placed in 100 μl of a medium supplementedwith a human recombinant interleukin-1β (IL-1β: *ZENZYME*) and a testcompound. After incubating for 3 weeks in total during which the culturemedium was replaced on the weekly basis, the total amount ofhydroxyproline liberated into the culture medium and the amount ofhydroxyproline remaining in the cartilage piece were determined and %collagen degradation was calculated. The collagen degradation inhibitingactivity of a test compound was determined according to the followingequation.

Equation: Collagen degradation inhibiting activity(%)=100×(Ci—Cs)/(Ci—Cc)

[1610] wherein Cc is % collagen degradation in the absence of both ofIL-1β and compound, Ci is % collagen degradation in the presence ofIL-1β, and Cs is a % collagen degradation in the presence of both ofIL-1β and a test compound.

[1611] The followings are the collagen degradation inhibiting activitiesof the compounds of Examples. TABLE 14 Cartilage collagen degradationinhibiting activity (degradation inhibiting activity at 1 μM ofcompound) Example % Inhibition 24 91 25 88 39 39 126 70 156 84

INDUSTRIAL APPLICABILITY

[1612] Since an inventive compound (I) or a salt thereof has anexcellent MMP inhibiting effect, especially MMP-13 inhibiting effect, itis useful as a safe prophylactic and therapeutic agent forosteoarthritis, rheumatoid arthritis, osteoporosis, cancer,periodontosis, corneal ulcer, pathologic bone resorption (such asBehcet's disease), nephritis, arteriosclerosis, pulmonary emphysema,cirrhosis, autoimmune disease (Crohn's disease and Sjogren's disease),cancer metastasis, contraception, etc.

1. A compound represented by Formula:

wherein ring a and ring b may be same or different and each is anoptionally substituted homocyclic or heterocyclic ring, wherein thesubstituents on ring A and ring B may be bound to each other and takentogether with ring A, ring B and X² to form a condensed ring, each r¹may be same or different and is a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, an optionally substitutedheterocyclic group or SR² (wherein R² is a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group or an optionallysubstituted heterocyclic group), X¹ is a bond, an optionally substituteddivalent C₁₋₃ aliphatic hydrocarbon group or —NR³— (wherein R³ is ahydrogen atom, an optionally substituted hydrocarbon group or an acylgroup), X² is a bond, an optionally substituted divalent C₁₃ aliphatichydrocarbon group, —NR⁴— (wherein R⁴ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an acyl group), —O— or —S(O)_(p)—(wherein p is 0, 1 or 2), each y may be same or different and is ahydrogen atom, an optionally substituted hydrocarbon group, a halogenatom, a carboxyl group, an acyl group, an optionally substituted hydroxygroup, an optionally substituted amino group, SR⁵ (wherein R⁵ is ahydrogen atom, an optionally substituted hydrocarbon group, an acylgroup or an optionally substituted heterocyclic group), an oxo group, athioxo group, an optionally substituted imino group, a nitro group or acyano group, each m may be same or different and is 0 or 1, n is aninteger of 1 to 3, q₁ is an integer of 1 to 2n+4, q₂ is an integer of 0to 2n+3, and the sum of q₁ and q₂ is 2n+4, provided that when ring B isa nitrogen-containing heterocyclic ring then X² binds to a positioncapable of being substituted except for a nitrogen atom on ring B, or asalt thereof.
 2. A compound according to claim 1 wherein each of ring Aand ring B is an optionally substituted benzene ring.
 3. A compoundaccording to claim 1 wherein each R¹ may be same or different and is ahydrogen atom, an optionally substituted lower alkyl group, —(C═O)—R⁶(wherein R⁶ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted amino group or an optionallysubstituted hydroxy group) or SR² (wherein R²has a meaning defined inclaim 1).
 4. A compound according to claim 1 wherein each R¹ may be sameor different and is represented by Formula:

wherein each symbol has a meaning defined in claim 1, or by formula:

wherein each symbol has a meaning defined in claim
 1. 5. A compoundaccording to claim 1 wherein X¹ is an optionally substituted methylenegroup.
 6. A compound according to claim 1 wherein X² is —O—.
 7. Acompound according to claim 1 wherein the group represented by Formula:

in Formula I is a group represented by Formula:

wherein each of R⁷ to R¹¹ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹² (wherein R¹² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group) and each of other symbols has a meaning defined inclaim
 1. 8. A compound according to claim 1 wherein the grouprepresented by Formula:

in Formula I is a group represented by Formula:

wherein each of R¹³ to R²⁵ may be same or different and each is ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted hydroxy group, an optionally substituted aminogroup or SR¹² (wherein R¹² is a hydrogen atom, an optionally substitutedhydrocarbon group, an acyl group or an optionally substitutedheterocyclic group) and each of other symbols has a meaning defined inclaim
 1. 9. A compound according to claim 1 wherein m is
 0. 10. Acompound according to claim 1 which is represented by Formula:

wherein each symbol has a meaning defined in claim
 1. 11. A method forproducing a compound represented by Formula:

wherein each symbol has a meaning defined in claim 1 or a salt thereof,comprising reacting a compound represented by Formula:

wherein L is a leaving group and each of other symbols has a meaningdefined in claim 1 or a salt thereof with a compound represented byFormula: R¹SH wherein R¹ has a meaning defined in claim 1 or a saltthereof.
 12. A method for producing a compound represented by Formula:

wherein each symbol has a meaning defined in claim 1 or a salt thereof,comprising reacting a compound represented by Formula:

wherein each symbol has a meaning defined in claim 1 or a salt thereof,or a compound represented by Formula:

wherein each symbol has a meaning defined in claim 1 or a salt thereof,with a compound represented by Formula: R¹SH wherein R¹ has a meaningdefined in claim 1 or a salt thereof.
 13. A pharmaceutical compositioncomprising a compound represented by Formula:

wherein ring A and ring B may be same or different and each is anoptionally substituted homocyclic or heterocyclic ring, wherein thesubstituents on ring A and ring B may be bound to each other and takentogether with ring A, ring B and X² to form a condensed ring, each R¹may be same or different and is a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, an optionally substitutedheterocyclic group or SR² (wherein R² is a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group or an optionallysubstituted heterocyclic group), X¹ is a bond, an optionally substituteddivalent C₁₋₃ aliphatic hydrocarbon group or —NR³— (wherein R³ is ahydrogen atom, an optionally substituted hydrocarbon group or an acylgroup), X2 is a bond, an optionally substituted divalent C₁₋₃ aliphatichydrocarbon group, —NR⁴— (wherein R⁴ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an acyl group), —O— or —S(O)_(p)—(wherein p is 0, 1 or 2), each Y may be same or different and is ahydrogen atom, an optionally substituted hydrocarbon group, a halogenatom, a carboxyl group, an acyl group, an optionally substituted hydroxygroup, an optionally substituted amino group, SR⁵ (wherein R⁵ is ahydrogen atom, an optionally substituted hydrocarbon group, an acylgroup or an optionally substituted heterocyclic group), an oxo group, athioxo group, an optionally substituted imino group, a nitro group or acyano group, each m may be same or different and is 0 or 1, n is aninteger of 1 to 3, q₁ is an integer of 1 to 2n+4, q₂ is an integer of 0to 2n+3, and the sum of q₁ and q₂ is 2n+4 or a salt thereof.
 14. Amatrix metalloprotease inhibitor comprising a compound according toclaim 13 or a salt thereof.
 15. A prophylactic and therapeutic agentagainst osteoarthritis, rheumatoid arthritis, osteoporosis, cancer,periodontosis or corneal ulcer comprising a compound according to claim13 or a salt thereof.
 16. A method for preventing and treatingosteoarthritis, rheumatoid arthritis, osteoporosis, cancer,periodontosis or corneal ulcer comprising administering a compoundaccording to claim 13 or a salt thereof.
 17. A use of a compoundaccording to claim 13 or a salt thereof for producing a prophylactic andtherapeutic agent against osteoarthritis, rheumatoid arthritis,osteoporosis, cancer, periodontosis or corneal ulcer.